Primary Plasma Cell Leukemia Outcomes Remain Dismal Despite Novel Agents and Hematopoietic Cell Transplantation

Background Primary plasma cell leukemia (pPCL) is a rare plasma cell neoplasm with a high mortality rate. There have been improvements in multiple myeloma (MM) outcomes with novel induction agents and use of hematopoietic cell transplantation (HCT) with maintenance, but similar progress has not been reported for pPCL. We examined the outcomes of pPCL patients receiving novel agents with autologous (autoHCT) or allogeneic (alloHCT) approaches as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) in the modern era. Methods From 2008 to 2015, 348 pPCL pts underwent HCT (N = 277 - autoHCT and 71 - alloHCT) with 45% and 48% having research level data available, respectively. Cumulative incidences of non-relapse mortality (NRM) and relapse/progression (REL), and probability of progression-free survival (PFS) and overall survival (OS) were calculated. Cox multivariate regression was used to model survival after autoHCT only. Median follow-up in autoHCT and alloHCT was 48 and 60 months, respectively. Results AutoHCT Cohort Median age was 60 years and 93% received HCT within 12 months of diagnosis with 76% after a single line of induction (Table 1). 35% had high risk cytogenetics. 23% received bortezomib, doxorubicin, cisplatin, cyclophosphamide, and etoposide (VDPACE). Moreover, 40% received bortezomib (BTZ) and immunomodulatory drug (IMIID)-based triplets. Disease status at HCT was VGPR or better in 47%. 27% received maintenance therapy. At 4 years post-HCT, NRM was 7% (4-11%), REL 76% (69-82%), PFS 17% (13-23%), and OS 28% (22-35%) (Figures 1A, 2A, 2B). Disease status ≥VGPR at HCT and Karnofsky Performance Score >90 significantly predicted superior OS in multivariate analysis. AlloHCT Cohort Median age was 53 years and 89% received HCT within 12 months of diagnosis (Table 1). 61% received a single alloHCT, while 39% used auto-alloHCT tandem approach. 42% had high-risk cytogenetics. 61% received total body irradiation with 44% receiving myeloablative conditioning. Use of VDPACE was higher at 41% in this cohort. VGPR status at HCT was similar (48%), while maintenance was used less often (12%). Grade II-IV acute GVHD occurred in 30% and chronic GVHD in 45%. At four years post-HCT, NRM was 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%) (Figures 1A, 1B, 2A, 2B). There were no differences in outcomes based on type of HCT. A comparison of post-HCT outcomes of CIBMTR pPCL patients from 1995 to 2006 showed that PFS and OS outcomes are inferior despite lower NRM in this modern cohort (Mahindra et al. Leukemia. 2012). In addition, analysis of SEER (1995-2009) and CIBMTR databases showed that use of HCT increased from 12% (7-21%) in 1995 to 46% (34-64%) in 2009. Conclusion More newly diagnosed pPCL patients are receiving modern induction regimens translating into a higher proportion receiving HCT, but without significant further benefit post-HCT. Post-HCT relapse remains the biggest challenge and further survival in pPCL will likely need a combination of targeted and cell therapy approaches. This study provides a benchmark for future HCT studies for pPCL. Disclosures Girnius: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dhakal:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria. Shah:University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Bioclinical: Consultancy; Autolus: Consultancy; Genzyme: Other: Speaker. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria.

Download Full-text

The Mutational Landscape of Primary Plasma Cell Leukemia

Blood ◽

10.1182/blood-2018-99-116758 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 114-114 ◽

Cited By ~ 1

Author(s):

Carolina D. Schinke ◽

Cody Ashby ◽

Yan Wang ◽

Ruslana G. Tytarenko ◽

Eileen Boyle ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Cell Leukemia ◽

Advisory Committees ◽

Kras Mutations ◽

Aggressive Disease ◽

Primary Plasma Cell Leukemia

Abstract Introduction: Primary Plasma Cell Leukemia (pPCL) is a rare form of multiple myeloma (MM) that is characterized by an aggressive disease course with >20% peripherally circulating plasma cells (PCs) and poor clinical outcome. Despite the advances of modern anti-MM therapy, pPCL patients continue to experience low median overall survival (OS) suggesting a distinct biological background. Due to its low incidence of 1-2% of all MM patients, studies on physiopathology remain challenging and are limited. The aim of this study was to elucidate the differences in biology and outcome between non-pPCL MM and pPCL, to determine the genetic landscape of pPCL and to identify distinct signatures and pathways that potentially could be used as therapeutic targets. Methods: We performed gene expression profiling (GEP; Affymetrix U133 Plus 2.0) of matched circulating peripheral PCs and bone marrow (BM) PCs from 13 patients. Whole exome sequencing (WES) was performed on purified CD138+ PCs from BM aspirates from 19 pPCL patients with a median depth of 61x. CD34+ sorted cells, taken at the time of stem cell harvest from the same 19 patients, were used as controls. Translocations and mutations were called using Manta and Strelka and annotated as previously reported. Copy number was determined by Sequenza. Results: GEP from the BM and circulating peripheral PCs showed that the expression patterns of the two samples from each individual clustered together, indicating that circulating PCs and BM PCs in pPCL result from the same clone and are biologically clearly related. The clinical characteristics from the patient cohort used for WES analysis were as follows: median age was 58 years (range 36-77), females accounted for 74% (14/19), an elevated creatinine level was found in 78% (14/18) and an elevated LDH level in 71% (10/14). All patients presented with an ISS stage of III. Median OS of the whole dataset was poor at 22 months, which is consistent with OS from previously reported pPCL cohorts. Primary Immunoglobulin translocations were common and identified in 63% (12/19) of patients, including MAF translocations, which are known to carry high risk in 42% (8/19) of patients [t(14;16), 32% and t(14;20), 10%] followed by t(11;14) (16%) and t(4;14) (10%). Furthermore, 32% (6/19) of patients had at least one MYC translocation, which are known to play a crucial role in disease progression. MYC breakpoints (8q24) were identified in 25% with Ig partner loci including IGH (5%), IGK (10%), and IGL (10%). The remaining samples had partner loci including FAM46C (5%), MYNN (5%), SPARC (5%), QRSL1 (5%), RNF126 (5%), PLXNA4 (5%) and CDH7 (5%). The mutational burden of pPCL consisted of a median of 98 non-silent mutations per sample, suggesting that the mutational landscape of pPCL is highly complex and harbors more coding mutations than non-pPCL MM. Driver mutations, that previously have been described in non-pPCL MM showed a different prevalence and distribution in pPCL, including KRAS and TP53 with 47% (9/19) and 37% (7/19) affected patients respectively compared to 21% and 5% in non-PCL MM. PIK3CA (5%), PRDM1 (10%), EP300 (10%) and NF1 (10%) were also enriched in the pPCL group compared to previously reported cases in non-pPCL MM. Biallelic inactivation of TP53 - a feature of Double Hit myeloma - was found in 6/19 (32%) samples, indicating a predominance of high risk genomic features compared to non-pPCL MM. Furthermore, analysis of mutational signatures in pPCL showed that aberrant APOBEC activity was highly prevalent only in patients with a MAF translocation, but not in other translocation groups. Conclusion: In conclusion we present one of the first WES datasets on pPCL with the largest patient cohort reported to date and show that pPCL is a highly complex disease. The aggressive disease behavior can, at least in part, be explained by a high prevalence of MAF and MYC translocations, TP53 and KRAS mutations as well as bi-allelic inactivation of TP53. It is of interest that only KRAS but not NRAS mutations are highly enriched in pPCL. From all highly prevalent genomic alterations in pPCL, only KRAS mutations offer a potential for already available therapeutically targeting with MEK inhibitors, which should be further explored. Disclosures Davies: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Honoraria; TRM Oncology: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Abbvie: Consultancy; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria. Barlogie:Multiple Myeloma Research Foundation: Other: travel stipend; ComtecMed- World Congress on Controversies in Hematology: Other: travel stipend; Millenium: Consultancy, Research Funding; European School of Haematology- International Conference on Multiple Myeloma: Other: travel stipend; International Workshop on Waldenström's Macroglobulinemia: Other: travel stipend; Celgene: Consultancy, Research Funding; Dana Farber Cancer Institute: Other: travel stipend; Myeloma Health, LLC: Patents & Royalties: : Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding.

Download Full-text

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Adults with Ph-like ALL

Blood ◽

10.1182/blood-2021-153125 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3955-3955

Author(s):

Ibrahim Aldoss ◽

Dongyun Yang ◽

Zhaohui Gu ◽

Vanina Tomazian ◽

Sally Mokhtari ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Relapse Rate ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Conditioning Regimen ◽

Disease Status ◽

R Package ◽

Genetic Alterations ◽

Advisory Committees

Abstract Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) represents 20% of newly diagnosed adults with B cell ALL (B-ALL), with increased frequency in adults with Hispanic ethnicity. Ph-like ALL harbors a diverse range of genetic alterations with CRLF2-rearrangement/overexpression (CRLF2r) being the most common one. When treated with chemotherapy, Ph-like ALL is associated with inferior response, high relapse rate, and low overall survival (OS). Allogenic hematopoietic cell transplantation (alloHCT) is a well-established curative modality for adults with high-risk ALL. Considering that Ph-like ALL is a high-risk leukemia subtype, it is appealing to recommend alloHCT consolidation routinely for this entity in adults. However, large datasets describing alloHCT outcomes in patients with Ph-like ALL is lacking. In this study, we retrospectively analyzed archived DNA samples from 125 consecutive adult patients with Ph-negative ALL who underwent alloHCT in complete remission (CR) at our center between 2006 and 2020. Classification of Ph-like versus non-Ph-like was performed according to WHO 2017 classification using accumulative results from RNAseq, conventional cytogenetics, FISH, and whole genome array studies. A proprietary RNA sequencing assay covering 1,188 genomic regions from 235 genes was designed to detect all the clinically significant fusions and expressions for Ph-like ALLs. In addition, an algorithm employing the RNAseq data was developed to further aid in classification of Ph-like ALL. Boruta feature selection (R package "Boruta" version 7.0.0) was used to identify the most informative genes for prediction with an out-of-bag error of 9.62%. The following 24 genes were identified: CCND2, SOX11, PAX5, DENND3, RARA, MME, ID4, SH3BP5, HOXA9, CA6, MUC4, CYB5R2, CD97, EPOR, IL2RA, RAB29, PDGFRA, MLLT4, RHOA, JAK2, DNM2, ASXL1, BCL2A1, and KDR. The results were used to predict Ph-like status by a Random Forest model (R package "randomForest" version 4.6-14) that generates a probability/similarity score of Ph gene expression profile (Ph score). The testing samples with Ph score over 50% and without other subtype-defining lesions are defined as Ph-like. We identified Ph-like genetic alterations in 66 (53%) patients, of whom 42 (66%) were carrying CRLF2r and 24 (36%) were non-CRLF2r. Compared to non-Ph-like ALL (n=59), Ph-like ALL patients were younger (42 vs 36 years old, p=0.022), more frequently Hispanic (56% vs 83%, p=0.003), less frequently carried high-risk cytogenetics (39% vs 9%, p<0.001), more frequently induced with pediatric-inspired regimens (25% vs 61%, p=0.003) and more likely required >1 regimen to achieve their first complete remission (CR1; 30% vs 55%, p=0.025). However, we did not detect any significant difference between the two groups in disease status (CR1 vs. CD2/3; p=0.81) or minimal residual disease clearance at the time of HCT (negative vs. positive; p=0.17), donor type (match related/unrelated vs mismatch vs haplo vs cord blood; p=0.88), conditioning regimen intensity (myeloablative vs non-myeloablative/ reduced intensity; p=0.59), GVHD prophylaxis (tacrolimus/sirolimus-based vs PTCy-based; p=0.84), Karnofsky Performance Status (KPS; p=0.24) or HCT comorbidity index (0 vs 1-2 vs >2; p=0.42). With the median follow-up of 3.2 years, we observed similar 3-years leukemia-free survival (LFS) (40% vs 47%; p=0.95), OS (44% vs 54%; p=0.96), relapse rate (33% vs 34%; p=0.96) and non-relapse mortality (NRM) (27% vs 19%; p=0.92) between non-Ph-like and Ph-like ALL patients, respectively. (Figure) In multivariable analysis, disease status at the time of HCT (HR=2.63, 95% CI: 1.57-4.41; p<0.001), donor type (p=0.049) and KPS (HR=2.22, 95% CI: 1.05-4.69; p=0.038) influenced OS. LFS was significantly influenced by disease status (HR=2.35, 95% CI: 1.45-3.80); p<0.001) and conditioning regimen intensity (HR=1.84, 95% CI: 1.11-3.04; p=0.017). Relapse rate was associated with disease status (HR=2.06, 95%CI: 1.11-3.84; p=0.23) and conditioning regimen intensity (HR=1.97, 95% CI: 1.03-3.75; p=0.40). Only KPS (HR=6.56, 95% CI: 2.48-17.36; P<0.001) was associated with NRM. In conclusion, our data suggest that alloHCT consolidation results in favorable outcomes in adult patients with Ph-like ALL with comparable outcomes to non-Ph-like ALL. Our data support utilization of alloHCT for adults with Ph-like ALL in CR. Figure 1 Figure 1. Disclosures Al Malki: Neximmune: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Hansa Biopharma: Consultancy; CareDx: Consultancy. Khaled: Omeros: Honoraria; Alexion: Honoraria, Speakers Bureau; Janssen: Current Employment; Astellas: Honoraria; Jazz: Honoraria. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Aribi: Seagen: Consultancy. Mei: BMS: Research Funding; Epizyme: Research Funding; TG Therapeutics: Research Funding; EUSA: Honoraria; Janssen: Honoraria; Morphosys: Research Funding; Beigene: Research Funding. Koller: Novartis: Consultancy. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Marcucci: Abbvie: Other: Speaker and advisory scientific board meetings; Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Pullarkat: AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Amgen, Dova, and Novartis: Consultancy, Honoraria.

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

First-Line Treatment and Management of Chronic Myeloid Leukemia (CML) in Clinical Practice: Update of > 1800 Patients (Pts) in the WORLD CML Registry

Blood ◽

10.1182/blood.v120.21.3750.3750 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3750-3750

Author(s):

Jorge E. Cortes ◽

Ricardo Pasquini ◽

Hagop M. Kantarjian ◽

David Joske ◽

Luis A Meillon ◽

...

Keyword(s):

Clinical Practice ◽

Board Of Directors ◽

Research Funding ◽

Disease Status ◽

First Line ◽

Employment Equity ◽

Advisory Committees ◽

Time Points ◽

The World ◽

Equity Ownership

Abstract Abstract 3750 Background: The WORLD CML Registry is a multinational, prospective registry established to longitudinally assess global patterns of current and evolving methods for diagnosis, treatment, and clinical outcome measures in pts with CML and to compare clinical practice patterns to management recommendations provided by the European LeukemiaNet (ELN; Baccarani M, et al. J Clin Oncol. 2009;27:6041–6051). Here, we report overall efficacy and safety data from this registry, as well as clinical monitoring practices and outcomes in the subgroup of pts with CML in chronic phase (CP) treated with first-line imatinib. Methods: Pts (≥ 16 y of age) with CML in CP, accelerated phase (AP), or blast crisis (BC) within 6 mo + 2 weeks of confirmed CML diagnosis were enrolled at sites in Latin America, Asia-Pacific, the United States, Russia, Turkey, the Middle East, and Africa. Baseline demographics and medical history were collected at enrollment; disease status and management information were collected at approximate 6-mo intervals or when there was a change in disease status/management. Adverse events (AEs) were collected only if they resulted in a dose/regimen change, nonadherence to treatment, or death. Results: A total of 1837 of the 1889 pts enrolled between February 2008 and December 31, 2010, were evaluable (ie, had confirmed informed consent forms and no protocol deviations) and are the basis for this analysis. Median age was 47 y (range, 16–92 y), and 58% of pts were male. CML diagnosis was established using hematologic (91% of pts), bone marrow (82%), cytogenetic (83%), and molecular (polymerase chain reaction [PCR]; 53%) assessments. Nearly all pts (94%) were initially diagnosed in CP (Table). As of the data cutoff (December 31, 2010), median overall survival (OS) and median event-free survival (EFS) in all pts were not reached. Estimated OS and EFS rates at 3 y were 90.4% and 74.8%, respectively. AEs reported in ≥ 1% of pts were thrombocytopenia (3%) and neutropenia (2%). In the CML-CP subgroup, imatinib (Glivec®/Gleevec®) was administered as first-line therapy (in clinical practice or in a clinical trial) to 63% of pts (n = 1083). Disease burden in CML-CP pts on imatinib over time was most commonly assessed via blood counts (Table). Cytogenetic and molecular assessments were used in a minority of CML-CP pts at most time points. Only 50% of pts had a disease assessment at 3 mo (hematologic, 49%; cytogenetic, 10%; molecular, 15%). Of the pts on first-line imatinib outside of a clinical trial setting (n = 1024), 95 (9%) had their dose increased, 77 (8%) had their dose decreased, and 82 (8%) were switched to nilotinib or dasatinib. In all CML-CP pts treated with first-line imatinib, estimated OS and EFS rates at 3 y were 92.1% and 76.6%, respectively (Table). Estimated OS and EFS rates at 3 y were higher in pts who had higher imatinib exposure (treatment received ≥ 85% of total days) vs pts who received imatinib treatment on < 85% of days. Conclusions: The majority of CML-CP pts treated with first-line imatinib did not have cytogenetic or molecular assessments in accordance with current ELN recommendations, particularly at early time points. Additionally, pts who had higher drug exposure to imatinib had higher estimated OS and EFS rates at 3 y than those who did not. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Piccolo:Novartis Pharma AG: Employment. Zernovak:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Sivarathinasami:Novartis Healthcare Pvt. Ltd,: Employment. Eng:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Kim:Novartis: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding; II-Yang: Consultancy, Honoraria, Research Funding. Hughes:Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding.

Download Full-text

A Novel Prognostic Model That Is Superior to FLIPI-1 and FLIPI-2 and Integrates Clinical and Treatment Factors to Predict Progression-Free Survival and Early Treatment Failure in Patients with Follicular Lymphoma in the GALLIUM Trial

Blood ◽

10.1182/blood-2018-99-114620 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2872-2872 ◽

Cited By ~ 2

Author(s):

Farheen Mir ◽

Andrew Grigg ◽

Michael Herold ◽

Wolfgang Hiddemann ◽

Robert Marcus ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Prognostic Model ◽

Low Risk ◽

Prognostic Variables ◽

Advisory Committees ◽

High Risk Disease ◽

Risk Patients ◽

Equity Ownership

Abstract Introduction: Progression of disease within 24 months of initial therapy (POD24) is associated with poor survival in patients with follicular lymphoma (FL). Existing prognostic models, such as FLIPI-1 and FLIPI-2, show poor sensitivity for POD24, and are derived from cohorts lacking bendamustine-treated patients. More accurate predictive models based on current standard therapies are needed to identify patients with high-risk disease. The Phase III GALLIUM trial (NCT01332968) compared the safety and efficacy of standard chemotherapy regimens plus rituximab (R) or obinutuzumab (G) in patients with previously untreated FL. Using GALLIUM data, we developed a novel risk stratification model to predict both PFS and POD24 in FL patients after first-line immunochemotherapy. Methods: Enrolled patients were aged ≥18 years with previously untreated FL (grades 1-3a), Stage III/IV disease (or Stage II with bulk), and ECOG PS ≤2, and required treatment by GELF criteria. Patients were randomized to receive either G- or R-based immunochemotherapy, followed by maintenance with the same antibody in responders. The chemotherapy arm (CHOP, CVP, or bendamustine) was selected by each study center. POD24 was defined as progressive disease or death due to disease within 24 months of randomization (noPOD24 = no progression or lymphoma-related death in that period). The most strongly prognostic variables, based on PFS hazard ratios, were estimated using penalized multivariate Cox regression methodology via an Elastic Net model. Selected variables were given equal weights, and a clinical score was formed by summating the number of risk factors for each patient. Low- and high-risk categories were determined using a cut-off that provided the best balance between true- and false-positives for PFS. PFS correlation and sensitivity to predict POD24 were assessed. The data used are from an updated GALLIUM efficacy analysis (data cut-off: April 2018; median follow-up: 57 months). Results: 1202 FL patients were enrolled. Based on data availability and biological plausibility (i.e. could reasonably be linked with high-risk disease), 25 potential clinical and treatment-related prognostic variables were entered into the Elastic Net model (Table). A model containing 11 factors was retained by the methodology and chosen as the best model (Table). Patients were categorized as 'low risk' if they scored between 0 and 3 (n=521/1000 patients with complete data) and as 'high risk' if they scored between 4 and 11 (n=479/1000 patients). At 2 years, the PFS rate was 84.5% in the whole FL population. Using our model, 2-year PFS for high-risk patients was 77% compared with 79.9% for FLIPI-1 and FLIPI-2. In low-risk patients, 2-year PFS was 92% compared with 87.9% for FLIPI-1 and 87.6% for FLIPI-2 (low-intermediate-risk patients). Our model increased the inter-group difference in 2-year PFS rate from 8% (FLIPI-1) and 7.7% (FLIPI-2) to 15%. At 3 years, the inter-group difference increased from 6.9% (FLIPI-1) and 9% (FLIPI-2) to 17% (Figure). Sensitivity for a high-risk score to predict POD24 was 73% using our model compared with 55% for FLIPI-1 and 52% for FLIPI-2 (based on 127 POD24 and 873 noPOD24 patients with complete data). Excluding patients who received CVP, which is now rarely used, resulted in an inter-group difference in PFS of 15% at 2 years and 16.8% at 3 years. A sensitivity analysis showed that inclusion of the 9 clinical factors only (i.e. removal of CVP and R treatment as variables) formed a more basic scoring system (low-risk patients, 1-3; high-risk patients, 4-9); the inter-group difference in PFS was 16.5% at 2 years and 17.6% at 3 years. However, sensitivity for POD24 decreased to 56%. Conclusion: Our clinical prognostic model was more accurate at discriminating patients likely to have poor PFS than either FLIPI-1 or FLIPI-2, and its prognostic value was sustained over time. Our model also identified the FL population at risk of POD24 with greater sensitivity. Variables such as age and bone marrow involvement were not retained by our model, and thus may not have a major impact in the current era of therapy. Factors such as sum of the products of lesion diameters were included, as this captures tumor burden more accurately than presence of bulk disease. Future studies will aim to improve the accuracy of the model by considering gene expression-based prognostic markers and DNA sequencing to form a combined clinico-genomic model. Disclosures Mir: F. Hoffmann-La Roche: Employment. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; Bayer: Consultancy, Research Funding. Marcus:F. Hoffman-La Roche: Other: Travel support and lecture fees; Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy. Seymour:Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bolen:Roche: Other: Ownership interests PLC*. Knapp:Roche: Employment. Launonen:Launonen: Other: Ownership interests none PLC; Travel, accommodation, expenses; Novartis: Consultancy, Equity Ownership, Other: Ownership interests none PLC; Travel. accommodation, expenses; Roche: Employment, Other: Travel, accommodation, expenses. Mattiello:Roche: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Oestergaard:Roche: Employment, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Casulo:Gilead: Honoraria; Celgene: Research Funding.

Download Full-text

Identifying Ultra-High Risk Smoldering Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-109709 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3192-3192 ◽

Cited By ~ 1

Author(s):

Theresia Akhlaghi ◽

Even H Rustad ◽

Venkata D Yellapantula ◽

Neha Korde ◽

Sham Mailankody ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Ultra High Risk ◽

Risk Of Progression ◽

Equity Ownership ◽

M Spike ◽

Risk Biomarkers

Abstract Introduction Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage to active multiple myeloma (MM), comprised by a heterogenous group of patients with varying rates of progression. While the overall yearly progression rate is 10% the first 5 years, some patients progress at a considerably higher rate. A study from the Mayo Clinic showed that in a subset of 21 patients defined by ≥60% monoclonal bone marrow plasma cells (BMPC), 95% progressed within 2 years. It was subsequently concluded by the International Myeloma Working Group (IMWG) that patients with biomarkers predictive of a 2-year progression rate at 80%, and a median time to progression at 12 months were at ultra-high risk of progression and should be considered to have MM requiring treatment despite being asymptomatic. In 2014, ultra-high risk biomarkers were incorporated in the definition of MM, including BMPC ≥60%, free light chain (FLC) ratio ≥100 and ≥2 focal lesions on magnetic resonance imaging (MRI). While the updated myeloma definition changed the diagnosis of some patients with ultra-high risk SMM to MM, there remain patients classified as SMM progressing at a very high rate. In the present study, we aimed at further identifying ultra-high risk biomarkers predictive of a high rate of progression to active MM. Methods Patients with SMM presenting to Memorial Sloan Kettering Cancer Center between the years 2000 and 2017 were identified and included in the study. Diagnosis of SMM and progression to MM requiring therapy was defined according to the IMWG criteria at the time of diagnosis. Baseline patient and disease characteristics were collected at date of diagnosis with SMM, including pathology reports, laboratory results and imaging data. Time to progression (TTP) was assessed using the Kaplan-Meier method with log-rank test for comparisons. Optimal cut-off values for continuous variables were assessed with receiver operating characteristics (ROC) curve. Patients who had not progressed by the end of study or were lost to follow up were censored at the date of last visit. Univariate Cox regression was used to estimate risk factors for TTP with hazard ratios (HR) and 95% confidence intervals (CI). Significant univariate risk factors were selected for multivariate Cox regression. Results A total of 444 patients were included in the study. Median follow-up time was 78 months. During the study period, 215 (48%) patients progressed to active MM, with a median TTP of 72 months. Cut-off points for BMPC, M-spike, and FLC ratio were determined with ROC curves to be 20%, 2 g/dL, and 18, respectively, for predicting high risk of progression. The following factors were associated with significantly increased risk of progression to active MM: BMPC >20%, M-spike >2g/dL, FLC ratio >18, immunoparesis with depression of 1 and 2 uninvolved immunoglobulins respectively, elevated lactate dehydrogenase, elevated beta-2-microglobulin, and low albumin (Table 1). In the multivariate model, BMPC >20% (HR 2.5, 95% CI 1.6-3.9), M-spike >2g/dL (HR 3.2, CI 1.9-5.5), FLC ratio >18 (HR 1.8, CI 1.1-3.0), albumin <3.5 g/dL (HR 3.9, CI 1.5-10.0), and immunoparesis with 2 uninvolved immunoglobulins (HR 2.3, CI 1.2-4.3), predicted a decreased TTP (Table 1). A total of 12 patients had 4 or 5 of the risk factors from the multivariate model, 8 of these did not meet the 2014 IMWG criteria for MM. These patients had a significantly shorter TTP than patients with less than 4 risk factors (median TTP 11 vs 74 months, p<0.0001, Figure 1). At 16 months, 82% of these patients had progressed, and within 2 years, 91% of the patients progressed. Only one patient remained progression free after 2 years, progressing at 31 months. Of patients with less than 4 risk factors, 19% progressed within the first 2 years. Conclusion In addition to baseline BMPC >20%, M-spike >2g/dL, FLC-ratio >18, we found that albumin <3.5g/dL and immunoparesis of both uninvolved immunoglobulins at the time of diagnosis with SMM were highly predictive of a decreased TTP to MM requiring therapy. These biomarkers are readily available and routinely assessed in clinic. Patients with 4 or 5 of these risk factors represent a new ultra-high risk group that progress to active disease within 2 years, further expanding on the definition of ultra-high risk SMM. In accordance with the rationale on ultra-high risk biomarkers as criteria established by the IMWG in 2014, such patients should be considered to have MM requiring therapy. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Takeda: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria. Lesokhin:Squibb: Consultancy, Honoraria; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Shah:Amgen: Research Funding; Janssen: Research Funding. Mezzi:Amgen: Employment, Equity Ownership. Khurana:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Werther:Amgen: Employment, Equity Ownership. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding.

Download Full-text

Elotuzumab As Post-Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Myeloma

Blood ◽

10.1182/blood-2019-129504 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3141-3141 ◽

Cited By ~ 2

Author(s):

Nikhita Gadi ◽

Linda Schmidt ◽

Jaeil Ahn ◽

Tianmin Wu ◽

Scott D. Rowley ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

Ultra High Risk ◽

Equity Ownership ◽

Baseline Characteristics

Introduction: Patients (pts) with high-risk multiple myeloma (HRMM) experience early disease progression post autologous stem cell transplant (ASCT). The median progression free survival (PFS) for HRMM pts undergoing ASCT with lenalidomide (len) maintenance ranges between 27 and 42 months in high risk pts and 22 months in ultra-high risk, defined by two or more adverse cytogenetic abnormalities such as: gain(1q), t(4;14), t(14;16),t(14;20), or del(17p)( Chakraborty et al, Leukemia,2018 and Jackson et al, Lancet, 2018). Elotuzumab, a humanized IgG kappa monoclonal antibody against SLAM-F7 (CS-1), is approved in combination with len and dexamethasone (ERd) in pts with relapsed MM (Dimopoulus et al, BJH, 2017). It directly activates natural killer (NK) cells and mediates myeloma cell death by antibody-dependent cell mediated cytoxicity. We hypothesized that administration of ERd as post-ASCT consolidation will enhance an immune-competent phenotype, by restoring NK cells and effector T-cell populations at a time of maximal disease de-bulking, and will ultimately improve outcomes among pts with HRMM. Methods: Thirty-one HRMM patients who achieved stable disease or better were treated beginning at 30-90 days post ASCT with ERd (29/31 pts) or elotuzumab/pomalidomide )/dex (EPd) (2/31 pts) between September 2016 and February 2019. With institutional review board approval, electronic medical records were reviewed for baseline characteristics, treatment history, adverse events (AE) while on therapy as defined by common terminology criteria for adverse events (CTCAE), and survival outcomes. Treatment with ERd or EPd was administered for 4 consecutive 28-day cycles per standard dosing regimens with a tapering or discontinuation of corticosteroids per investigator discretion with cycles 3 and 4. HRMM was defined by any of the following: ISS or Revised-ISS stage 3, CD-138 selected FISH with del 17p, 1q21 gain, t(4;14), t(14;16), and t(14;20), cytogenetics with 13q del or complex karyotype, and/or high-risk gene expression profile score. Ultra-HR pts were defined by having both del 13q and 1q21 gain by FISH based on recent unpublished COMPASS data. Minimal residual disease (MRD) was evaluated upon achievement of very good partial remission or complete remission using 10-color multiparametric flow cytometry. PFS was measured using the log-rank test. Response criteria was defined per International Myeloma Working Group criteria. Results: Baseline characteristics of all 31 patients are shown in Table 1. Thirty-four percent were ISS-3, 71% (22/31 pts) had high-risk FISH, of which 19% were ultra-high risk (6/22 pts). Seven pts (22.6%) underwent tandem-ASCT pre-consolidation. Of the 8 pts who had GEP testing, 2 (25%) were high risk. Best response to treatment by cycle is depicted in Table 2. Consolidative ERd/EPd deepened response compared to post-ASCT with 71.4% vs 19.4% achieving stringent complete remission (sCR). Post-consolidation, 19.3% vs 12.9%, pre-consolidation, achieved MRD negativity. With a median follow-up of 24.8 months, median PFS was 31.4 months (Figure 1). There was no significant association between median PFS and variables such as tandem ASCT and ultra-HR using multivariate cox regression. Although all pts experienced at least one AE while on therapy, only 1 patient (3.22%) experienced a grade 3 AE. Hematologic AEs included: anemia (48%), neutropenia (45%), and thrombocytopenia (52%), while the most common non-hematologic AEs included: fatigue (32%), malaise (23%), and back pain (19%). One patient experienced a serious AE (SAE) which was PCP pneumonia requiring hospitalization, resulting in early discontinuation from therapy. There was no treatment-related mortality. Conclusion: ERd or EPd as 4 months of fixed duration consolidation therapy post-ASCT resulted in a median PFS of 31.4 months amongst pts with HRMM, similar to or perhaps surpassing historical reports of HRMM pts receiving lenalidomide maintenance until progression. This therapy may offer comparable, if not superior, outcomes while having the advantage of allowing for significant time without therapy and perhaps improving quality of life and financial toxicity. This study is limited due to its retrospective nature. Larger prospective studies evaluating fixed duration ERd/EPd in HRMM patients post ASCT should be conducted. Disclosures Rowley: Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Goldberg:COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership. Siegel:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Biran:Bristol Meyers Squibb: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Merck: Research Funding.

Download Full-text

Efficacy of Venetoclax Combination Therapy with Hypomethylating Agents in Patients with Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2019-129514 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5089-5089 ◽

Cited By ~ 1

Author(s):

Varun Mittal ◽

Mimi Lo ◽

Lloyd E. Damon ◽

Karin L. Gaensler ◽

Thomas G. Martin ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Hypomethylating Agents ◽

Advisory Committees ◽

Allogeneic Hct ◽

Acute Myeloid

Introduction: Venetoclax (VEN), a selective BCL-2 inhibitor, in combination with hypomethylating agents (HMA) has high efficacy in treatment-naïve elderly patients with acute myeloid leukemia (AML). The role for VEN in patients with relapsed/refractory (R/R) AML, myelodysplastic syndrome (MDS), or other myeloproliferative neoplasms remains incompletely defined. In particular, the efficacy of VEN+HMA has not been studied systematically in patients who experience AML relapse following allogeneic hematopoietic cell transplantation (HCT). Method: All patients treated with VEN+HMA (azacitidine or decitabine) for R/R de novo or secondary AML or progressive MDS following allogeneic HCT were identified and reviewed retrospectively. All included AML patients had overt clinical relapse with ≥ 5% bone marrow blasts or extramedullary disease biopsy proven to be AML. Patients were included in this analysis if they received at least 14 days of VEN therapy. Results: Eleven patients with median age 66 (range 25-75) were treated for R/R AML post-allogeneic HCT. Transplant characteristics included use of reduced intensity conditioning in 10/11 (91%), matched sibling donors in 5/11 (45%), matched unrelated donors in 5/11 (45%), and cord blood in 1/11 patients. The median time from HCT to relapse/disease progression was 7 months (range 3-36). Two patients had extramedullary relapse only, and the remainder had marrow involvement. Eight patients (73%) received azacitidine and 3 (27%) received decitabine in combination with VEN. All but two patients (82%) had prior HMA exposure and most received VEN+HMA as initial post-transplant salvage therapy (64%). Only one patient received donor lymphocyte infusion in conjunction with VEN+HMA therapy, and none proceeded to a second allotransplant. Nine patients (82%) experienced an objective response, which included 4 CR/CRi (36%) and 5 PR/SD (45%). In patients with CR/CRi, three patients had adverse risk cytogenetics and one had a favorable risk profile at diagnosis consisting of normal cytogenetics with an isolated NPM1 mutation. All patients who failed to remit with VEN+HMA had intermediate- or high-risk genetic features. The median number of treatment cycles given was 3 (range 1-20). Median survival was 11 months and estimated 6-month and 12-month survival was 82% and 36%, respectively. Three patients remain alive with median 16.5 months follow-up (range 2.5-32). Conclusion: Venetoclax in combination with HMA is a viable salvage option in patients with relapsed AML or progressive MDS after allogeneic HCT, including those with prior exposure to HMA. Although one patient in this cohort sustained long term complete remission, overall prognosis remains dismal in this high-risk patient population and improved treatment options for relapsed/refractory AML following alloHCT remain needed. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Olin:MedImmune: Research Funding; Ignyta: Research Funding; Clovis: Research Funding; AstraZeneca: Research Funding; Revolution Medicine: Consultancy; Daiichi Sankyo: Research Funding; Astellas: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Mirati Therapeutics: Research Funding; Spectrum: Research Funding. Smith:Astellas Pharma: Research Funding; Abbvie: Research Funding; fujiFilm: Research Funding; Revolution Medicines: Research Funding. Logan:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pharmacyclics: Research Funding; Astellas: Research Funding; Jazz: Research Funding; Kite: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; TeneoBio: Consultancy; Kiadis: Consultancy; Kadmon: Research Funding; Abbvie: Consultancy.

Download Full-text

Real-World Data on Clinical Characteristics, Prognosis and Outcome of Primary Plasma Cell Leukemia: A Study of the Greek Myeloma Study Group in the Era of Novel Agents

Blood ◽

10.1182/blood.v128.22.4490.4490 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4490-4490

Author(s):

Eirini Katodritou ◽

Evangelos Terpos ◽

Sossana Delimpasi ◽

Maria Kotsopoulou ◽

Eurydiki Michalis ◽

...

Keyword(s):

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Performance Status ◽

Novel Agents ◽

Induction Treatment ◽

Real World Data ◽

Advisory Committees ◽

Primary Plasma Cell Leukemia

Abstract Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with poor outcome. We and others have previously demonstrated in a limited number of pPCL patients that novel agents and mainly bortezomib-based regimens (BBR) improve response rates and survival; in addition, two recent prospective studies have confirmed the efficacy of lenalidomide-dexamethasone and BBR respectively, followed by autologous transplantation (ASCT) in pPCL; however, the prognostic impact of the induction therapy was not evaluated in both studies. Herein, we explored the clinical characteristics and the impact of current treatments and biological markers on the outcome of an extended cohort of primary PCL (pPCL) patients treated upfront with novel agents, outside clinical trials. We analyzed the medical records of 50 patients with pPCL (M/F: 25:25; median age 65.5 years, range: 32-86 years; IgG: 19, IgA: 9, light-chain only: 14, IgD: 2, non-secretory: 6; ISS1: 5, ISS2: 16, ISS3: 29) out of 2711 myeloma patients (1.8%), registered in the Greek Myeloma study group database, between 2000-2015. Eastern Cooperative Group (ECOG) performance status was ≥2 in 52% of patients; 77% of patients presented with lytic bone disease and 11% with bone or soft tissue palsmacytomas. Bence-Jones protein was present in 68% of patients; 53% of patients had abnormal lactate dehydrogenase (LDH); 28% had hypercalcemia and 68% had hemoglobin <10 g/dL; fluorescent in situ hybridization (FISH) or conventional karyotype were available in 32/50 (64%) patients; high risk features were present in 65% of patients; 60% of patients had CD56(-) peripheral blood plasma cells; 49/50 patients received therapy: Thirty-eight out of 49 (77.5%) patients received BBR, one patient was treated with the combination of melphalan, prednisone and thalidomide and 10 patients with conventional chemotherapy (C/T); 14/38 (37%) of patients treated with BBR and one patient treated with C/T underwent ASCT consolidation; one patient received in addition an allogeneic transplantation; 48/49 treated patients were evaluated for response: 38/48 patients (79%) achieved objective response (≥PR) and 35% displayed at least very good partial response (≥vgPR), including 17% complete responses (CR). Achievement of ≥vgPR significantly correlated with BBR followed by ASCT (p=0.02). Median time to response was 2 months (range 1-11). After a median follow up of 61 months (95% CI: 34.5-87.4), 38 (76%) patients have died (disease progression: 18, infection: 16, other causes: 4) and 12 patients remain alive. Early mortality (≤1 month) occurred in 3/38 (6%) deceased patients; 31/38 patients who responded in induction treatment progressed; 27/31 patients who progressed received 2nd line treatment (lenalidomide-based: 7, BBR: 16, C/T: 4). Progression-free survival was 12 months (95% CI: 8.5-15.4) and it was marginally longer in patients treated with BBR+ASCT vs. others (18 months vs. 10 months, p=0.07). Median OS was 17 months (95% CI: 13-21 months) and it was double in patients treated with BBR+ASCT compared to others (33 months vs. 16 months); median survival after PCL progression was only 7 months (95% CI: 3-11 months). In the univariate analysis, performance status, LDH, induction treatment with BBR, or treatment with BBR+ASCT and quality of response (≥vgPR vs. <vgPR) were independent prognostic factors for OS. In the multivariate analysis quality of response and LDH were the only significant predictors for OS (p<0.05). The median OS for patients who achieved ≥vgPR was 39 months (95% CI: 22-55) vs. 13 months (95% CI: 9-17) for those achieved <vgPR (p=0.02, HzR: 0.46). The median OS for patients with LDH ≥300 U/L was 11 months (95% CI: 7-15 months) vs. 24 months (95% CI: 8-40 months) for those with LDH <300U/L (p=0.03, HzR: 0.5). These real-world data, based on the largest reported national multicenter series of pPCL patients to-date, support that treatment with BBR plus ASCT is the best currently available option that offers deep and durable responses and reduces early mortality in this setting. Quality of response and high LDH were the strongest independent prognostic factors for OS. We conclude that pPCL requires an aggressive upfront therapeutic approach with a bortezomib-based regimen followed by ASCT that would lead to maximum response and eventually to prolonged OS. Disclosures Katodritou: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genesis: Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Terpos:Celgene: Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria. Delimpasi:Janssen: Honoraria; Genesis: Honoraria; Amgen: Honoraria. Kotsopoulou:Genesis: Honoraria. Kyrtsonis:Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Roche: Honoraria; Amgen: Honoraria; Takeda: Consultancy, Honoraria; Genesis: Honoraria. Kastritis:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genesis: Consultancy, Honoraria. Dimopoulos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Pmd-107: Marizomib, Pomalidomide and Low Dose-Dexamethasone Combination Study in Relapsed/Refractory Multiple Myeloma (NCT02103335): Full Enrollment Results from a Phase-1 Multicenter, Open Label Study

Blood ◽

10.1182/blood.v128.22.3326.3326 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3326-3326 ◽

Cited By ~ 4

Author(s):

Andrew Spencer ◽

Simon Harrison ◽

Jacob P. Laubach ◽

Jeffrey Zonder ◽

Ashraf Z Badros ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Employment Equity ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Heavily Pretreated ◽

Equity Ownership

Abstract Marizomib (MRZ) is a novel, irreversible, pan subunit proteasome inhibitor (PI) with preclinical evidence demonstrating in vitro and in vivo activity in multiple myeloma (MM). This study was designed to evaluate the safety and antimyeloma activity of pomalidomide (POM), MRZ and low dose dexamethasone (Lo-DEX) (PMD) in patients with relapsed and refractory multiple myeloma (RRMM). Thirty-eight heavily pretreated patients with RRMM were enrolled [dose-escalation cohort (n=14); recommended Phase 2 dose (RP2D) cohort (n=24)]. IV MRZ (0.3 to 0.5 mg/m2) was administered on Days (D) 1, 4, 8, 11; POM (3 or 4 mg) on D1 through 21; and Lo-DEX (5 or 10 mg) on D1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, 23 of every 28-D cycle. Patients received a median of 4 (range 1-9) prior lines of therapy; 100% received prior lenalidomide (LEN) and bortezomib (BTZ), 34% carfilzomib (CFZ), and 50% thalidomide. 53% of patients were refractory to both LEN and BTZ and 21% were refractory to LEN, BTZ, and CFZ. There were no dose limiting toxicities during the study. The most common study treatment related ≥Grade 3 adverse events (AEs) were neutropenia (11/38 pts: 29%), pneumonia (4/38 pts 11%), anemia (4/38 pts; 11%), thrombocytopenia (4/38 pts; 11%), and febrile neutropenia (2/38 pts; 5%), with two grade 4 AEs (neutropenia related to POM and viral infection related to DEX), and one grade 5 AE (cardio-respiratory arrest from a suspected PE related to POM). Overall, MRZ was well tolerated, did not add to the incidence or severity of POM/Lo-DEX AEs and the regimen may have fewer hematological and infectious AEs compared to that observed with POM/Lo-DEX. MRZ pharmacokinetic analysis revealed that it was rapidly cleared with a short T1/2 (6.2-11mins) and a large volume of distribution (41-86L) suggesting extensive tissue distribution. Pharmacodynamic analysis demonstrated rapid and robust inhibition of chymotrypsin-like activity in both packed whole blood (PWB) and peripheral blood mononuclear cells (PMBCs), reflecting the irreversible binding nature of MRZ. Evolving inhibition of trypsin-like and caspase-like proteasome activity was also observed in PWB and PBMC with continued dosing. The overall response rate (ORR) and clinical benefit rate (CBR) for the 36 response evaluable patients was 53% (19/36) and 64% (23/36), respectively (Table 1). Subpopulation analysis demonstrated an ORR of 50% (5/10) in high risk cytogenetic patients, 56% (10/18) in LEN/BTZ refractory patients, 71% (5/7) in LEN/BTZ/CFZ refractory patients and 80% (8/10) in CFZ refractory patients. These data compare favorably against POM/Lo-Dex with a near doubling of ORR in both the total patient population and the double refractory patients. Substantial activity in high-risk patients that are triple refractory and in patients that are refractory to CFZ in prior last regimen was observed. MRZ activity in RRMM patients exposed and/or refractory to multiple PIs is likely a consequence of its unique pan proteasome subunit inhibitory actions. In conclusion, MRZ in combination with POM and Lo-DEX was well tolerated and demonstrated promising activity in heavily pretreated, high-risk RRMM patients. Table 1 Table 1. Disclosures Harrison: Janssen-Cilag: Research Funding, Speakers Bureau; Celgene: Honoraria. Zonder:Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Khot:Amgen: Honoraria; Janssen: Consultancy; Pfizer: Speakers Bureau. Anderson:C4 Therapeutics: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; C4 Therapeutics: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Oncoprep: Equity Ownership; Millennuim: 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; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. MacLaren:Triphase Accelerator: Employment, Equity Ownership. Reich:Triphase Accelerator: Consultancy. Trikha:Encycle Therapeutics: Consultancy, Equity Ownership; Triphase Accelerator: Employment, Equity Ownership. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Download Full-text