A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci

Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma (MM)

CLR 131 (Iopofosine I-131) Treatment in Triple Class Refractory and Beyond Multiple Myeloma Patients: Preliminary Efficacy and Safety Results from the Phase 2 Clover-1 Trial

Abstract Background: Phospholipid ethers (PLE) provide a novel mechanism to target tumor cells. Tumor cells contain increased amounts of lipid rafts in their cell membranes, which are thought to enhance signaling and resist apoptosis. Phospholipid drug conjugates (PDC) are specifically designed to have high affinity for lipid rafts which upon binding results in trans-membrane inversion with the ability to deliver an attached therapeutic directly to the cytosol. Iopofosine I-131 (formerly identified as CLR 131) is a novel PDC delivering I-131 as a targeted tumor cell radiotherapy. Iopofosine I-131 is being examined in relapsed or refractory multiple myeloma (RRMM) patients through an open-label, Phase 2 trial, CLOVER-1 (NCT02952508). Methods: The primary objective of this study is to determine the safety and efficacy of Iopofosine I-131 in heavily pretreated MM patients. Eligibility criteria for MM patients include progression or relapsed disease that is refractory to at least 1 proteasome inhibitor and 1 immunomodulatory agent unless intolerable/ineligible to receive such agents with no upper limit to the number of prior lines of therapy. Iopofosine I-131 is administered in up to 4 IV infusions (15-20 min) over 3 months, with doses given 1-2 weeks apart each cycle for a maximum of 2 cycles, along with dexamethasone 40 mg weekly (20 mg in patients &gt; 75), for up to 12 weeks. Following iopofosine I-131 administration, no other antineoplastic or targeted therapy was given until clinically indicated by the investigator. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the 2016 International Myeloma Working Group criteria. Results: Eleven patients with at least triple class refractory (immunomodulatory agent, proteasome inhibitor and monoclonal antibody) MM have been enrolled in this Phase 2 study with data current as of 28 May 2021. Patients had a median age of 72 (range 34-77), mean prior regimens of 7.2 (range 3-17) and received a mean total body dose of 75.4 mCi (range 59.7-118.7) of iopofosine I-131. The overall response rate (ORR) was 45.5% (5/11), the clinical benefit rate (CBR) was 72.7% (8/11) and disease control rate (DCR) was 100%. Median progression free survival (PFS) was 3.4 months. In a subset of patients who are quad/penta drug refractory, efficacy increased with an ORR of 80.0% (4/5) and CBR of 100% (5/5). The primary treatment emergent AEs in patients with MM included cytopenias (87.5%), in line with prior experience with iopofosine I-131. The most commonly observed cytopenias included Grade 3 or 4 thrombocytopenia (62.5%), anemia (62.5%), neutropenia (62.5%) and decreased white blood cell count (50%). There were no infusion-related reactions or AEs. Conclusions: Initial results for iopofosine I-131 show efficacy with a promising ORR of 45.5% and a CBR or 72.7% in heavily pretreated triple class refractory multiple myeloma patients. Interestingly, iopofosine I-131 showed its highest efficacy in patients that were quad/penta drug refractory with ORR of 80%, highlighting its potential as a later line therapy. Iopofosine I-131 is a novel cancer radiotherapeutic that may provide benefit to patients that are refractory/unresponsive to traditional MM therapies. CLOVER-1 is actively enrolling MM patients that are at least triple class refractory across the United States. Disclosures Ailawadhi: AbbVie: Consultancy; Pharmacyclics: Consultancy, Research Funding; Ascentage: Research Funding; Cellectar: Research Funding; GSK: Consultancy, Research Funding; Genentech: Consultancy; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Sanofi: Consultancy; Medimmune: Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Xencor: Research Funding; Takeda: Consultancy; Beigene: Consultancy. Stiff: CRISPR: Consultancy; Gamida-Cell, Atara, Amgen, Incyte, Takeda, Macrogenetics, Eisai: Research Funding; Cellectar: Research Funding. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Cull: Aptevo: Research Funding. Friend: Cellectar: Current Employment. Longcor: Cellectar: Current Employment. Oliver: Cellectar: Current Employment. </jats:sec

Survival trends in glioblastoma and association with treating facility volume

Glioblastoma (GBM) is one of the most lethal cancers. Various prognostic factors impact the survival of GBM patients. To further understand this extremely poor prognosis disease, we evaluated the effect of the treatment facility volumes on overall survival (OS) over the years, especially after the approval of multimodality therapy using temozolomide (TMZ) in 2005. National Cancer Data Base (NCDB) was utilized to identify GBM cases from 2004 through 2013 using ICD-O-3 code 9440/3 to identify eligible patients. We focused on studying the association between treatment facility volume and OS after adjusting for the patient-, disease-, and facility-characteristics. A total of 60,672 eligible GBM patients with median age of 65 years, treated at 1166 facilities were included in this analysis. The median annual facility volume was 3 patients/year (range: 0.1–55.1) and median OS was 8.1 months. There was an improvement in OS across all facilities after 2005, when multimodality therapy with TMZ was approved. Treatment at quartile 4 centers (Q4; \u3e7 patients/year) was independently associated with decreased all-cause mortality in a multivariate analysis (Q3 hazard ratio [HR]: 1.11, 95% CI 1.09, 1.13; Q2 HR: 1.15, 95% CI 1.12, 1.19; Q1 HR: 1.25, 95% CI 1.17, 1.33). Treatment facility volume independently affects OS among GBM patients. Factors that are variable in high- and low-volume centers should be addressed to mitigate outcome disparities

Immunophenotyping of Waldenströms Macroglobulinemia Cell Lines Reveals Distinct Patterns of Surface Antigen Expression: Potential Biological and Therapeutic Implications

<div><p>Waldenströms macroglobulinemia (WM) is a subtype of Non-Hodgkin’s lymphoma in which the tumor cell population is markedly heterogeneous, consisting of immunoglobulin-M secreting B-lymphocytes, plasmacytoid lymphocytes and plasma cells. Due to rarity of disease and scarcity of reliable preclinical models, many facets of WM molecular and phenotypic architecture remain incompletely understood. Currently, there are 3 human WM cell lines that are routinely used in experimental studies, namely, BCWM.1, MWCL-1 and RPCI-WM1. During establishment of RPCI-WM1, we observed loss of the CD19 and CD20 antigens, which are typically present on WM cells. Intrigued by this observation and in an effort to better define the immunophenotypic makeup of this cell line, we conducted a more comprehensive analysis for the presence or absence of other cell surface antigens that are present on the RPCI-WM1 model, as well as those on the two other WM cell lines, BCWM.1 and MWCL-1. We examined expression of 65 extracellular and 4 intracellular antigens, comprising B-cell, plasma cell, T-cell, NK-cell, myeloid and hematopoietic stem cell surface markers by flow cytometry analysis. RPCI-WM1 cells demonstrated decreased expression of CD19, CD20, and CD23 with enhanced expression of CD28, CD38 and CD184, antigens that were differentially expressed on BCWM.1 and MWCL-1 cells. Due to increased expression of CD184/CXCR4 and CD38, RPCI-WM1 represents a valuable model in which to study the effects anti-CXCR4 or anti-CD38 targeted therapies that are actively being developed for treatment of hematologic cancers. Overall, differences in surface antigen expression across the 3 cell lines may reflect the tumor clone population predominant in the index patients, from whom the cell lines were developed. Our analysis defines the utility of the most commonly employed WM cell lines as based on their immunophenotype profiles, highlighting unique differences that can be further studied for therapeutic exploit.</p></div

Presence of stem-cell markers on RPCI-WM1.

<p>A total of 8 surface antigens that are typically expressed on the surface of stem cells were examined. Notably, more than 90% of RPCI-WM1 cells gated were CD110+low and CXCR4/CD184+low. A comparison of these and the remaining stem-cell antigens in BCWM.1 and MWCL-1 cell lines is presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122338#pone.0122338.t004" target="_blank">Table 4</a>.</p

WM-specific antigen expression compared across RPCI-WM1, BCWM.1 and MWCL-1 cell lines.

<p>Fluorescein (FITC), phycoerythrin (PE), phycoerythrin—cyanine 5 (PC5) or allophycocyanin (APC) conjugates of various antibodies were used as presented above. All cell lines were negative for CD10 and 11c. Blue line indicates RPCI-WM1 antigen expression, red line indicates MWCL-1 antigen expression and green line indicates antigen expression in BCWM.1 cell line. Only BCWM.1 an MWCL-1 were CD19+, CD20+ and FMC7+. Expression of CD138 and κ-light-chain was seen only on MWCL-1 and RPCI-WM1 cells. CD28 expression was markedly more observable on RPCI-WM1 tumor cells as compared to MWCL-1 or BCWM.1.</p