bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical, genomic, and imaging predictors of malignancy: Analysis of the first U.S. cooperative group prospective clinical trial in asymptomatic monoclonal gammopathies (SWOG S0120).
Authors: Dhodapkar Madhav V. , Sexton Rachel , Waheed Sarah , Usmani Saad Zafar , Papanikolaou Xenofon Dimitrios , Nair Bijay P. , Petty Nathan , Shaughnessy John D. , Hoering Antje , Crowley John , Orlowski Robert Z. , Barlogie Bart
Published: March 2020

8515

Background: Asymptomatic monoclonal gammopathies (AMG) are the most common plasma cell dyscrasia classified as either monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic multiple myeloma (AMM). Clinical outcome in AMGs can be highly variable and there is an unmet need to identify newer clinical, genomic and imaging parameters from prospective studies to guide patient management. Methods: We analyzed clinical, genomic and imaging data from AMG patients (n=334) enrolled in a prospective observational clinical trial (S0120) conducted under the auspices of SWOG. Baseline data from clinical variables, as well as gene expression profiles of purified tumor cells and the findings on magnetic resonance imaging (MRI) were correlated with the risk of progression to symptomatic myeloma (MM) requiring therapy. Results: In addition to serum M spike, percent bone marrow plasma cells and the ratio of involved/uninvolved serum free light chains, the level of serum beta-2-microglobulin was associated with an increased risk of progression to clinical myeloma requiring therapy. Gene expression profiles (GEP) of purified tumor cells revealed that all of the known molecular GEP subtypes of human MM are also represented in the precursor phase. An increased risk score (> - 0.26) based on a 70-gene signature (GEP70) was an independent predictor of the risk of progression to clinical MM requiring therapy. The presence of focal lesions on MRI also conferred an increased risk of disease progression but was not independent of other clinical and genomic features. Conclusions: These data represent the first comprehensive evaluation of clinical, genomic and imaging features of AMGs in the context of a prospective US-cooperative group trial, and demonstrate that while all genetic subtypes of MM have a precursor phase, genetic signatures previously associated with high risk myeloma also predict the risk of progression to clinical malignancy requiring therapy. These findings suggest the need to integrate both clinical assessment of tumor bulk and genomic properties of tumor cells in the clinical management of these patients. Clinical trial information: NCT00900263.
Second primary malignancies (SPM) in newly diagnosed myeloma (MM) patients treated with lenalidomide (Len): Meta-analysis of 6,383 individual patient data (IPD).
Authors: Palumbo Antonio , Bringhen Sara , Rajkumar Vincent , Lupparelli Giulia , Usmani Saad Zafar , Waage Anders , Larocca Alessandra , van der Holt Bronno , Musto Pellegrino , Evangelista Andrea , Zweegman Sonja , Dimopoulos Meletios A. , Hajek Roman , Cavo Michele , Lonial Sagar , Ciccone Giovannino , Boccadoro Mario , Barlogie Bart , Sonneveld Pieter , McCarthy Philip L.
Published: March 2020

8517

Background: An increased risk of SPM in MM pts treated with len has been reported. We performed an IPD metanalysis to estimate the incidence of SPM according to len exposure. Methods: Randomized studies of MM, from PubMed and ASCO/IMW/ASH (after 2000), that met the following criteria, were included: randomization to treatment with len (len-trials); randomization to treatment including new drug but not len (no-len-trials); available SPM data. Primary aim was to estimate cumulative incidence of SPMs by len exposure, corrected for death (competing event). Results: Data from 6,383 pts (3,218 from 8 len-trials, 3,165 from 10 no-len-trials) were analyzed. Median age was 69 years. During follow-up (median=30 mos) 420 (6.6%) SPMs were reported: 188 (2.9%) hematologic and 232 (3.6%) solid cancers. Solid tumors occurred with similar incidence in all groups. Incidence of hematologic SPM was significantly higher in patients receiving len (3.2 vs 1.1, p=0.04), but risk is limited to patients treated with melphalan+len (4.1, 95%CI: 2.4-5.8) with no excess in other combinations (len without melphalan: 1.2, 0.0-2.6; melphalan without len: 1.1, 0.0-2.7) (p=0.003). The cumulative incidence of death for any cause was much higher than the risk of SPM. Conclusions: The risk of hematologic SPMs was higher in pts receiving melphalan+len. The benefit/risk profile of len treatment remains positive. Cumulative incidence (%) of SPMs and death (95%CI). [Table: see text]
Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM).
Authors: Goy Andre , Ribrag Vincent , Varga Andrea , Witzig Thomas E. , Ocio Enrique M. , Paz-Ares Luis G. , Mita Monica M. , Meyer Tim , Munster Pamela N. , Mahipal Amit , Delord Jean-Pierre , Arkenau Hendrik-Tobias , Gutierrez Martin , James Angela , Wong Lilly , Xu Shuichan , Wu Xiaoling , Carmichael James , Chopra Rajesh , Hege Kristen
Published: March 2020

8522

Background: CC-223 is an ATP-competitive inhibitor of the mTOR kinase, including both TORC1 and TORC2 complexes. CC-223 was selected to address resistance of rapamycin analogues mediated by TORC2 activation. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with advanced DLBCL, MM and select solid tumors were enrolled in parallel expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 35 subjects were enrolled including DLBCL (21) and MM (14). Results in solid tumor cohorts are reported separately. The most common (> 20%) related adverse events (all grades) were fatigue, hyperglycemia, rash, anorexia, nausea, vomiting and diarrhea. In addition, related serious adverse events included infection (2), pneumonitis (1), renal insufficiency (2), pancreatitis (1) and thrombocytopenia (1). CC-223 dose reduction was required in 9 subjects (27%), usually during cycle 1 or 2, and 4 additional subjects with DLBCL dropped out during cycle 1 due to toxicity. Systemic exposure was similar between the two tumor cohorts and was associated with inhibition of TORC1 (p4EBP1) and TORC2 (pAKT) biomarkers in blood cells. Reduction in glucose uptake (32 – 98% decrease) on PET imaging at day 15 was observed in 7/7 DLBCL subjects with results currently available. Three of 17 evaluable subjects with DLBCL had partial responses (PR) after 2 cycles; two with rapid and near complete regression (> 90%) of target lesions by CT and PET with PR confirmed and treatment ongoing at 6 and 8 cycles. Both had failed multiple prior treatment regimens (5 and 3, respectively), including autologous stem cell transplant (ASCT). No responses were observed in 10/14 evaluable subjects with MM although 2 subjects have prolonged stable disease (SD) with treatment ongoing at 12 and 14 cycles. Conclusions: Encouraging signals of biomarker and clinical activity were observed in DLBCL, including two near complete responses, which are ongoing. Due to dose reductions and interruptions, a starting dose of 30 mg QD is recommended for future studies. Clinical trial information: NCT01177397.
Pomalidomide plus low-dose dexamethasone (POM + LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM): Impact of cytogenetics in MM-003.
Authors: Goldschmidt Hartmut , Dimopoulos Meletios A. , Weisel Katja C. , Moreau Philippe , Lacy Martha , Song Kevin W. , Delforge Michel , Karlin Lionel , Banos Anne , Rocafiguera Albert Oriol , Yu Xin , Sternas Lars , Jacques Christian , Zaki Mohamed H. , San-Miguel Jesùs F.
Published: March 2020

8528

Background: RRMM patients (pts) who fail lenalidomide (LEN) and bortezomib (BORT) have poor prognosis. High-risk cytogenetics predict shorter survival. POM + LoDEX has demonstrated efficacy in pts with prior LEN and BORT and high-risk cytogenetics. MM-003 is an open-label, multicenter, phase III trial comparing POM + LoDEX vs. HiDEX in RRMM pts who failed LEN and BORT treatment (Tx) and have progressed on their last therapy. Methods: Pts must have been refractory to the last prior Tx (progressive disease [PD] during or within 60 days) and failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination). Randomization was 2:1 to POM 4 mg D1–21 + DEX 40 mg (20 mg for pts aged > 75 y) weekly; or DEX 40 mg (20 mg for pts aged > 75 y) D1–4, 9–12, and 17–20 (28-day cycles). Tx continued until PD or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS). Secondary endpoints included OS and AEs. This analysis examined pts meeting modified high-risk cytogenetic criteria—del(17p13) and/or t(4p16/14q32). Results: 302 pts received POM + LoDEX, and 153 pts received HiDEX. 225 and 107 pts, respectively, were evaluable for cytogenetics. Baseline characteristics were similar. Median PFS and OS were significantly longer with POM + LoDEX vs. HiDEX, regardless of cytogenetic risk (Table). The most common grade 3/4 AEs were neutropenia, anemia, and infection (Table). Discontinuation due to AE was low: 4% vs. 6% (high risk) and 10% vs. 4% (standard risk). Conclusions: Median PFS and OS were significantly longer with POM + LoDEX vs. HiDEX in pts with cytogenetically-defined high-risk disease, consistent with results from the intent-to-treat population. Tolerability was acceptable. POM + LoDEX should be considered a new Tx option in pts failing LEN and BORT. Clinical trial information: NCT01311687. [Table: see text]
Clinical response by baseline characteristics in patients (pts) with relapsed and bortezomib (BTZ)-refractory multiple myeloma treated with panobinostat (PAN), BTZ, and dexamethasone (DEX; PANORAMA 2).
Authors: Alsina Melissa , Richardson Paul Gerard Guy , Schlossman Robert L. , Weber Donna M. , Coutre Steven E. , Gasparetto Cristina , Mukhopadhyay Sutapa , Ondovik Michael S. , Khan Mahmudul H , Paley Carole S. , Lonial Sagar
Published: March 2020

8531

Background: In PANORAMA 2, PAN + BTZ + DEX recaptured responses in heavily pretreated pts with BTZ-refractory MM; overall response rate (ORR), clinical benefit rate (CBR), and progression-free survival (PFS) were 34.5%, 52.7%, and 5.4 months, respectively. Here, we evaluate clinical response per baseline characteristics. Methods: Response was based on European Group of Blood and Marrow Transplantation 1998 criteria. High-risk cytogenetics was defined as del(17p), t(4;14), or t(14;16). Quality of life (QoL) was measured with Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) v4.0 scale. Results: Response rate trended higher in pts whose prior BTZ therapy was not their last line of therapy (Table). Although no trend in response rate was noted, PFS appeared longer in pts progressing within 60 days of their last BTZ-containing regimen than in those progressing on their last BTZ-containing regimen. In the 14 pts with high-risk cytogenetics, ORR was 42.9% and CBR was 71.4%. The mean FACT/GOG-Ntx subscale did not exhibit a clinically meaningful change from baseline (mean ± standard deviation [SD], 114.2 ± 21.1; n = 41) to cycle 9 day 1 (day 169; 104.2 ± 15.4; n = 16) as determined by 50% SD threshold for minimally important difference. Other QoL parameters were similarly unchanged. Conclusions: PAN + BTZ + DEX demonstrated activity regardless of baseline demographics in heavily pretreated pts with BTZ-refractory MM. Clinical trial information: NCT01083602. [Table: see text]
Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (Pts) with relapsed and refractory multiple myeloma (RRMM): MM-002 phase II age subgroup analysis.
Authors: Jagannath Sundar , Hofmeister Craig C. , Baz Rachid C. , Siegel David Samuel DiCapua , Vij Ravi , Chen Christine , Lonial Sagar , Anderson Kenneth Carl , Chen Min , Zaki Mohamed H. , Richardson Paul Gerard Guy
Published: March 2020

8532

Background: POM demonstrated clinical efficacy and favorable tolerability in RRMM pts previously treated with lenalidomide (LEN) and bortezomib (BORT), in the randomized, multicenter, open label MM-002 phase II trial. This analysis evaluated whether the efficacy and tolerability of POM+LoDEX treatment is consistent across age subgroups. Methods: Pts with RRMM who had received ≥ 2 prior therapies, including LEN and BORT, and were refractory to their last regimen were randomized to either POM+LoDEX (POM 4 mg/day, days 1–21 of a 28-day cycle; LoDEX 40 mg/week) or POM alone. End points included progression-free survival (PFS), response rate (based on EBMT criteria), response duration, and safety. A post-hoc analysis based on age (≤ 65 vs. > 65 yrs) was conducted. Results: A total of 221 pts with a mean age of 64 yrs (range 34–88) were randomized to POM+LoDEX (n = 113) or POM (n = 108). The efficacy outcomes and the most common treatment emergent grade 3/4 adverse events (AEs) for the age subgroups according to treatment arm are presented in the Table. Conclusions: Regardless of age (≤ 65 vs. > 65 yrs), POM with or without LoDEX was effective and generally well tolerated in heavily pretreated RRMM pts who had already received LEN and BORT. POM with or without LoDEX represents a new clinical option for pts previously treated with numerous lines of therapy. Updated data will be presented at the meeting. Clinical trial information: NCT00833833. [Table: see text]
Combined analysis of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma.
Authors: Witzig Thomas E. , Vose Julie , Zinzani Pier Luigi , Habermann Thomas Matthew , Tuscano Joseph M. , Sinha Rajni , Williams Michael E. , Drach Johannes W. , Ramchandren Rod , Kalayoglu Besisik Sevgi , Zhang Lei , Cicero Sherri , Fu Tommy , Goy Andre
Published: March 2020

8533

Background: Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma (NHL) with poor prognosis. The immunomodulatory agent lenalidomide shows consistent activity with tolerable safety in multiple phase II studies of relapsed/refractory aggressive NHL (NHL-002 and NHL-003) and MCL post-bortezomib (MCL-001). This pooled analysis further examined the efficacy and safety of single-agent lenalidomide in patients with relapsed/refractory MCL. Methods: Single-agent lenalidomide was given 25 mg/d PO on days 1-21 of 28-day cycles as tolerated for 52 weeks (NHL-002) or until disease progression (NHL-003 and MCL-001). All MCL patients received ≥1 prior treatment, including bortezomib in MCL-001. Efficacy data were examined by independent central review for MCL-001 and NHL-003 and by investigators for NHL-002. Results: 206 patients with relapsed/refractory MCL were studied. The median age was 67 y (range 33-84; 63% ≥65 y), 91% stage III/IV disease and 51% had received ≥4 prior regimens (76% prior bortezomib). Overall response rate (ORR) with lenalidomide was 32% (10% CR/CRu), with a median time to response of 2.1 months and median duration of response (DOR) of 16.6 months (not yet reached in patients with CR/CRu; Table). Kaplan-Meier estimates for median PFS and OS were 5.4 and 23.9 months, respectively. Mean daily dose of lenalidomide was 21 mg. Grade 3/4 AEs included neutropenia (44%), thrombocytopenia (29%), anemia (11%), and fatigue (7%). Other any-grade AEs included tumor flare reaction (7%), venous thromboembolic events (7%), and invasive second primary malignancies (3%). Conclusions: Lenalidomide produced rapid and durable responses in patients with relapsed/refractory MCL, and exhibited a predictable safety profile among 3 phase II studies of lenalidomide in heavily pretreated patients, including prior treatment with bortezomib. Clinical trial information: MCL-001: NCT00737529; NHL-002: NCT00179660; NHL-003: NCT00413036. [Table: see text]
Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up.
Authors: Jakubowiak Andrzej J. , Dytfeld Dominik , Griffith Kent A. , Jasielec Jagoda , McDonnell Kathryn , Lebovic Daniel , Vesole David H , Jagannath Sundar , Chottiner Elaine G. , Anderson Tara B. , Detweiler-Short Kristen , Stockerl-Goldstein Keith , Ahmed Asra Z. , Jobkar Terri L. , Durecki Diane E. , Mietzel Melissa A , Couriel Daniel R. , Vij Ravi , Kaminski Mark Stefan
Published: March 2020

8543

Background: We previously reported results from a phase 1/2 trial of CRd in NDMM (NCT01029054), demonstrating a high rate (42%) of stringent complete response (sCR) and overall favorable efficacy /safety after a median of 12 cycles of treatment (tx) and a median follow-up of 13 mo (Jakubowiak et al Blood, 2012). Here we report updated results after extended tx and additional 12 mo of follow-up. Methods: Patients (pts) received 28-day (d) cycles of carfilzomib (CFZ) 20–36 mg/m2 IV (d1, 2, 8, 9, 15, 16), lenalidomide (LEN) 25 mg PO (d1–21), and dexamethasone 40/20 mg PO wkly (cycles 1–4/5–8). For cycles 8–24, CRd was given with a modified CFZ schedule (d1, 2, 15, 16) and then LEN alone after cycle 24. Stem cell transplant was an option after cycle 4. Response was assessed by IMWG plus nCR. Results: As of Nov 2012, 53 pts had received a median of 22 CRd cycles (range 2–24); 7 pts opted for transplant; 24 continued LEN maintenance for median 8 mo (range 1–10). Median follow-up was 25 mo (range 5–37). With extended tx, the CR rate was 64%; sCR improved from 42% to 53%, ≥nCR from 62% to 72%, and ≥VGPR from 81% to 87% (follow-up 13 vs 25 mo); ≥PR remained at 98%. Immunophenotypic CR (IMWG) was achieved in 22/26 evaluated pts. Of pts in sCR, 25% had high-risk cytogenetics per IMWG. In pts who did not proceed to transplant (n=46), the sCR was 59%, CR 70%, ≥nCR 78%, ≥VGPR 91%, and ≥PR 100%. Over the course of tx, depth of response improved. Median time to ≥VGPR was 4 cycles (range 2–17), ≥nCR 4.5 cycles (range 2–15), and sCR 10 cycles (range 4–30); 2 pts converted to sCR during LEN maintenance. At 2 years, the estimated PFS rate was 94% and OS was 98%; for pts with sCR, rates were 96% and 100%, respectively. Adverse event types, rates, and dose modifications during extended tx were comparable with those previously reported. There was 1 death off study due to disease progression. Conclusions: Extended follow-up showed that depth of response continued to improve over the course of prolonged CRd tx, resulting in exceptional CR, sCR, and PFS. Extended tx continued to be well tolerated. The results compare favorably with historical studies in both transplant and non-transplant NDMM. Clinical trial information: NCT01029054.
Comparative outcomes of splenectomy and rituximab-based chemotherapy in elderly patients with splenic marginal zone lymphoma.
Authors: Olszewski Adam J.
Published: March 2020

8549

Background: Despite advances in diagnosis and therapy, over 50% of patients with splenic marginal zone lymphoma (SMZL) undergo splenectomy. The objective of this retrospective study was to compare outcomes in SMZL patients undergoing surgery or rituximab-containing chemoimmunotherapy (RCIT) based on the Surveillance, Epidemiology, and End Results-Medicare linked database. Methods: Records of 521 SMZL patients diagnosed between 2000 and 2007 were extracted, excluding cases with incomplete Medicare coverage. Two treatment arms were defined by receipt of RCIT or splenectomy within 2 years of diagnosis. Factors confounding treatment selection or prognosis were balanced in both arms using a propensity score. The primary endpoint was lymphoma-related death, estimated using competing risk models, with overall survival (OS) and toxicities as secondary endpoints. Results: Of the 341 eligible patients (median age, 77 years), 67 (20%) were untreated, while 169 (50%) underwent splenectomy and 97 (28%) chemotherapy (64% single-agent rituximab) at median 1.4 months from diagnosis. Stage IE, treatment in a teaching hospital and good performance status were associated with a preference for splenectomy. There was no evidence of significantly different risk of lymphoma-related death after treatment with RCIT rather than surgery (hazard ratio, HR, 1.10, 95%CI 0.56-2.18, P=0.78). There was an excess of early mortality after splenectomy (7% within 90 days) but more later events with RCIT (OS at 3 years 69% vs. 67%, respectively). More patients required chemotherapy after surgery (38%) than vice versa (14%, P<0.001). Nursing home admissions were more common after splenectomy (22%, P=0.03). There were more inpatient hospitalizations after multidrug RCIT (P=0.003), but not after rituximab alone (P=0.65). Conclusions: Although SMZL is considered indolent, most elderly patients required treatment soon after diagnosis in this population-based study. Survival outcomes were similar after either RCIT or splenectomy. Complications of surgery or combination chemotherapy are significant, suggesting rituximab alone as a more suitable option in elderly patients.
Dose-dense R-CHOP (administered every 2 weeks) with sargramostim in patients with newly diagnosed diffuse large B-cell lymphoma.
Authors: Chaudhary Preeti , Groshen Susan G. , Tsao-Wei Denice D , Siddiqi Imran , Duddalwar Vinay , Berman Nancy , Duran Christine , Wang Teh-Chun , Tulpule Anil
Published: March 2020

8554

Background: R-CHOP administered every 3 weeks is standard of care for the treatment of diffuse large B-cell lymphoma (DLBCL). There are conflicting reports regarding the superiority of dose dense (DD) regimen (R-CHOP administered every 2 weeks), compared to the standard R-CHOP regimen. In a Phase II study, the tolerability and efficacy of DD-RCHOP+Sargramostim was evaluated. Methods: All patients received intravenous rituximab, 375 mg/m2; cyclophosphamide, 750 mg/m2; doxorubicin, 50 mg/m2 and vincristine, 1.4 mg/m2 on day 1; prednisone 100 mg orally on days 1-5 and sargramostim 250 mg/m2subcutaneously on days 3-13. Chemotherapy cycles were repeated every 2 weeks. Results: We studied50 newly diagnosed, previously untreated DLBCL patients (median age 54.1 years, range 21.4-80.3 years). Stage III and IV disease was noted in 12 (24%) and 29 (58%) patients, respectively. Baseline characteristics included the following: high-intermediate or high-risk IPI score (n=38, 76%), extranodal involvement (n=32, 64%), bone marrow infiltration (n=5, 10%), B-symptoms (n=23, 46%), median LDH level (272, range 118-3797) and good baseline performance status (n=45, 90%). The median follow up from the start of treatment was 12.7 months (range 0.1-41.4 months). Among the 46 patients evaluated for response, complete response (CR) or unconfirmed CR (CRu) was observed in 36 (78%) patients, partial response (PR) or an unconfirmed PR in 9(20%) patients and 1 patient had stable disease. The probability of overall survival (OS) at 18 months was 0.84. The probability of disease free survival in complete responders at 9 months was 0.89. Neutropenia was the most common hematological toxicity and accounted for delays in 40 (20%) treatment cycles. There were no episodes of fever/sepsis in the 33 patients (66%) with grade 3 or 4 neutropenia. IgG, IgA and IgM levels decreased during therapy and returned to normal in 2-4 months post therapy. No opportunistic infections were reported. Conclusions: The administrationof DD-RCHOP+Sargramostim regimen is safe, tolerable and effective in patients with newly diagnosed DLBCL. However, neutropenic episodes were significant, accounting in many cases for treatment delays.
Certification and role of local pathologists for diffuse large B-cell lymphoma (DLBCL) subtyping and eligibility determination in the phase II PYRAMID study.
Authors: Said Jonathan W. , Reeves James Andrew , Flinn Ian , Tulpule Anil , Robles Robert Leon , Flowers Christopher , DiBella Nicholas J. , Kolibaba Kathryn S. , Venugopal Parameswaran , Kolevska Tatjana , De Vos Sven , Jaye David L. , Esseltine Dixie , Mulligan George , Corvez Maria Margarita , Eckardt John R. , Brockman Bryan , Chico Isagani M. , Leonard John , Kussick Steven
Published: March 2020

8559

Background: The role of local pathologists in promoting patient (pt) accrual and evaluating eligibility criteria involving a complicated immunohistochemical (IHC) algorithm has rarely been investigated. The phase II PYRAMID trial (NCT00931918) is assessing R-CHOP ± bortezomib for newly diagnosed pts with non-germinal-center B-cell (non-GCB) subtype DLBCL. In this trial, local pathologists were encouraged to perform DLBCL subtyping at the point of biopsy, identify suitable pts for the trial, and facilitate accrual. Methods: Determination of GCB vs non-GCB subtype is per the Hans method, an algorithm based on IHC for CD10, BCL-6, and IRF4/MUM1. In stage 1, pathologists demonstrated IHC subtyping proficiency by evaluating a tissue microarray (TMA) of 12 DLBCL cases; those with ≥80% of samples in agreement with central lab results were certified for determining trial eligibility. In stage 2, to broaden participation, pathologist certification occurred via teleconference outlining trial eligibility criteria, tissue subtyping requirements, and determining pathologists’ experience with the Hans method. Results: 182 pathologists have been certified for local subtyping, 50 via TMA and 132 by teleconference. 66/88 active study sites have ≥1 certified pathologist. Only 1 of the 10 top enrolling sites lacks a certified pathologist. 52% (84/162) of pts have been enrolled based on local pathologist subtyping prior to central lab confirmation. Discordance with central lab results occurred in 9/84 cases (11%). Enrollment rates pre- and post-local pathologist certification were 0.053 and 0.096 pts/site/month; an improvement of 81%. Trial accrual correlates with the presence of a certified local pathologist (p=0.0026). The rate of ineligible GCB cases sent for central lab testing was lower from sites with a certified pathologist (23% [69/299 cases] vs 38% [40/106 cases] for sites without). Conclusions: Engagement of local pathologists in trials requiring pathology selection can significantly improve accrual. This study demonstrates the effectiveness of various training modalities in improving selection by local pathologists using a complex IHC algorithm. Clinical trial information: NCT00931918.
Y90-ibritumomab tiuxetan (Y90-IT) and high-dose melphalan as conditioning regimen before autologous stem cell transplantation (ASCT) for elderly patients with lymphoma in relapse or resistant to chemotherapy: A feasibility trial (SAKK 37/05).
Authors: Voegeli Michele , Rondeau Stephanie , Berardi Simona , Lerch Erika , Wannesson Luciano , Pabst Thomas , Rentschler Jochen , Bargetzi Mario , Jost Lorenz M. , Ketterer Nicolas , Bischof Delaloye Angelika , Ghielmini Michele E. G.
Published: March 2020

8560

Background: Standard conditioning regimens for ASCT are often not tolerated by elderly patients. Single agent high-dose melphalan has been shown to be safe and active in elderly patients with multiple myeloma. Y90-IT is a well-tolerated lymphoma treatment and feasible in the transplantation setting. We therefore investigated this combination of high-dose melphalan and Y90-IT as a conditioning regimen for elderly patients. Methods: Patients ≥65 years with relapsed or chemotherapy resistant CD20-positive lymphoma in PR or CR after salvage chemotherapy could be enrolled prior to stem cell mobilization. Myeloablation regimen consisted of standard dose Y90-IT followed by melphalan at escalating doses (100, 140, 170 and 200mg/m2, with a 3+3 phase I design) and by ASCT. The primary objective was to identify the MTD of melphalan in combination with standard dose Y90-IT (as defined < 1 DLT in 3 patients); secondary endpoints were toxicity and CR rate 100 days after transplantation. Results: Between 2006-2012 twenty patients were included. Median age was 72 years (range 66-77). One patient was considered retrospectively ineligible and was evaluable for toxicity but not for DLT. Thirteen patients received the treatment and were transplanted. Eleven patients were evaluable for DLT. No DLT occurred. Non-hematological grade 3 or higher treatment related adverse events were: infection (n=6, including 2 cases of febrile neutropenia), diarrhea (n=3), mucositis, anorexia, viral hepatitis, hypokalemia, dehydration and multi-organ failure (n=1). Seven patients did not start treatment because of mobilization failure (n=3), progressive disease (n=2), worsening of cardiac failure (n=1) and grade 3 dyspnea (n=1). Seven patients achieved a CR/CRu and 2 patients were stable 100 days after transplantation. Conclusions: The combination ofstandard dose Y90-IT and high dose melphalan (200mg/m2) is a safe and feasible conditioning regimen before ASCT for patients ≥65 years. The results show promising activity. Clinical trial information: NCT00392691.
Different safety profiles of first-line bendamustine-rituximab (BR), R-CHOP, and R-CVP in an open-label, randomized study of indolent non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL): The BRIGHT study.
Authors: MacDonald David , van der Jagt Richard , Burke John M. , Kahl Brad S. , Wood Peter , Hawkins Tim E. , Hertzberg Mark , Kwan Yiu-Lam , Simpson David , Craig Michael , Kolibaba Kathryn S. , Issa Samar , Clementi Regina , Hallman Doreen M. , Munteanu Mihaela C. , Chen Ling , Flinn Ian
Published: March 2020

8565

Background: The BRIGHT study demonstrated that first-line BR was non-inferior to R-CHOP/R-CVP in terms of complete remission rate in indolent NHL and MCL. This is the first detailed analysis of the safety and tolerability of the study regimens. Methods: Patients were preselected for R-CHOP or R-CVP, and then randomized to 6-8 cycles of BR (28-d cycle) or the preselected standard regimen (21-d cycles). BR dosing was bendamustine 90 mg/m2/d as a 30-min infusion on days 1 and 2 plus rituximab 375 mg/m2given before bendamustine on day 1. Colony stimulating factors (CSFs) and antiemetics were given per local standards. Results: In patients preselected for R-CHOP, 103 received BR and 98 R-CHOP. In patients preselected for R-CVP, 118 received BR and 116 R-CVP. For all regimens, ≥ 88% of patients received the planned 6 cycles. Main differences in adverse events (AEs), all grades, are shown in the Table. Incidence of grade 3/4 AEs was 69% for R-CHOP vs 56% BR, and 50% for R-CVP vs 56% BR. Grade 3/4 drug hypersensitivity, neuropathy, and rash were infrequent. Antiemetic use was similar between groups except use of aprepitant as an adjunct to 5-HT3 antagonists was higher with R-CHOP (23% [19% in cycle 1]) than BR (9% [2%]) or R-CVP (3% [2%]). CSF use was higher with R-CHOP (61%) than BR (29%) or R-CVP (27%). Analyses of event prevalence over the treatment period and by region will also be presented. Conclusions: BR, R-CHOP, and R-CVP have significantly distinct AE profiles. More nausea, vomiting, and hypersensitivity occurred with BR while more constipation, neuropathy, and alopecia occurred with RECHOP/R-CVP. Support: Teva BPP R&D, Inc. Clinical trial information: NCT00877006. [Table: see text]
Differential impact of sex in young and elderly patients with DLBC: Correlation with rituximab (R) pharmacokinetics.
Authors: Pfreundschuh Michael , Mueller Carsten , Zeynalova Samira , Held Gerhard , Poeschel Viola , Zwick Carsten , Rixecker Tanja , Schmitz Norbert , Murawski Niels ,   German Non-Hodgkin Lymphoma Study Group (DSHNHL)
Published: March 2020

8570

Background: Sex and weight independently influence R clearance in elderly DLBCL pts (Mueller et al., Blood 2012). Methods: We analyzed the impact of sex on R pharmacokinetics and outcome of 1,222 elderly pts of the RICOVER-60, 823 young (18 to 60 years) aaIPI=0,1 pts of the MInT, and 375 aaIPI=2,3 pts of the Mega-CHOEP trials. R pharmacokinetics was determined by ELISA in 33 young and 49 elderly patients. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling software (NONMEM VI). Results: R clearance was independent of tumor mass (IPI), but weakly correlated (0.2, R2linear=0.045) with increasing age in male, and moderately inversely correlated (-0.5, R2linear=0.207) with age in female DLBCL patients, resulting in similar R clearances in young female and male patients (9.88 vs. 10.38 ml/h; p=0.238), but a significantly faster R clearance in elderly males compared to females (10.50 vs 8.25 ml/h; p=0.006). In the RICOVER-60 trial, elderly females had a higher 3-year PFS (68% vs. 61%) and OS (74% vs. 68%) than male pts. due to a greater outcome improvement by the addition of R in females. In a multivariable analysis adjusting for IPI, the hazard for progression in male compared to female pts. was not significantly increased after CHOP (HR=1.1; p=0.348), but was significantly higher after R-CHOP (OR=1.6; p=0.004). In contrast, young males treated in the MInT and Mega-CHOEP trials benefitted as much as females from the addition of rituximab, with a similar hazard for male pts. after CHOP and R-CHOP (HR=1.2) with no significant difference to female patients (HRPFS=1.2, p=0.552; HROS=1.0; p=0.898). Conclusions: While no differences in R clearance and benefit from rituximab were found in young female compared to male patients, the reduced benefit of adding R to CHOP in elderly male DLBCL pts. who have a shorter rituximab serum half life and hence lower serum levels suggests that this subpopulation is suboptimally dosed when R is given based on body surface area at 375 mg/m2. Ongoing studies of the DSHNHL investigate whether higher R doses for pts. with a shorter R serum half life can improve the outcome of the respective patients. Supported by Deutsche Krebshilfe and Roche.
Prognostic value of PET/CT scans on early chemo-cycle in diffuse large B-cell lymphoma: Prospective study.
Authors: Huang He , Lin Jia Tian , Guo Cheng-cheng , Shrestha Dr.Prem Raj , Liu Tingzhi , Tian Ying , Liang Chao Yong , Li Xue Ying , Zhang Mengping , Hong Huang Ming , Lin Tongyu
Published: March 2020

8573

Background: To evaluate the prognostic value of positron emission tomography/computed tomography (PET/CT) scan on early chemo-cycle in newly-diagnosed diffuse large B cell lymphoma (DLBCL) patients. Also to distinguish the variation in outcome of early-responder (ER), late-responder (LR) and non-responder (NR). Methods: Newly diagnosed 149 DLBCL patients were treated with R-CHOP regimen for 2-8 cycles (mean: 5.49 cycles) in our center (Feb 2008–Jan 2013). The median age at diagnosis was 47 years (range, 17-80 years); 78 males (52.35%) and 71 females (47.65%); 63 stage I-II (42.3%) and 86 stage III-IV (57.7%); 45 B symptoms (30.2%); 90 IPI 1-2 scores (60.4%) and 59 IPI 3-5 scores (39.6%). All the patients with bulky disease, extranodal invasions and residual disease underwent baseline PET/CT scan and repeated after every 2 chemo-cycles. Results: After 2 subsequent cycles, the PET/CT evaluation showed complete remission (CR) in 82/149 (early-responder, 55.03%), and non-CR in 67/149 (44.97%) patients. Among 67 non-CR patients, 39 achieved CR (late-responder), 21 partial remission (PR), 3 stable disease (SD) and 4 progressive diseases (PD) (non-responder). After a follow-up of median 618 days (range 45-1816 days), the 1st and 2nd year progression-free survival (PFS) rate in NR were significantly different from ER (61.3% vs 92.6% , 52.5% vs 86.6%, p < 0.001) and LR (61.3% vs 91.6%, 52.5% vs 75.9%, p=0.023), and no significant differences were found between ER and LR (p=0.329). The 1st and 2nd year overall survival (OS) were 98.5%, 91.9% in ER; 97.3%, 97.3% in LR and 89.8%, 60.0% in NR respectively with significant differences between NR and ER (p=0.005), between NR and LR (p=0.008), but there was no statistically significant difference between ER and LR (p=0.558). The 1st and 2nd year disease free survival (DFS) rate did not differ between ER and LR (92.6% vs 84.6%, 86.9% vs 76.7%, p=0.250). Conclusions: The PET/CT findings in early chemo-cycle response might predict PFS advantage, but the difference of DFS and OS between ER and LR were not so obvious, and NR showed poor prognosis according to our current data. Clinical trial information: CTR-TRC-11001687.
Long-term safety and efficacy of pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in relapsed and refractory multiple myeloma (RRMM) patients enrolled in the MM-002 phase II trial.
Authors: Siegel David Samuel DiCapua , Richardson Paul Gerard Guy , Vij Ravi , Hofmeister Craig C. , Baz Rachid C. , Jagannath Sundar , Chen Christine , Lonial Sagar , Jakubowiak Andrzej J. , Bahlis Nizar J. , Song Kevin W. , Belch Andrew , Raje Noopur S. , Shustik Chaim , Lentzsch Suzanne , Chen Min , Zaki Mohamed H. , Anderson Kenneth Carl
Published: March 2020

8588

Background: MM-002 is a randomized, open-label, multicenter phase II trial evaluating the safety and efficacy of POM with or without LoDEX in advanced RRMM pts. Methods: Pts who had received ≥ 2 prior therapies, including lenalidomide (LEN) and bortezomib (BORT), and were refractory to their last treatment were randomized to POM+LoDEX (POM 4 mg/day, days 1–21 of a 28-day cycle; LoDEX 40 mg/week) or POM alone. End points included progression-free survival (PFS), response rate (according to EBMT criteria and investigator assessment), response duration, overall survival (OS), and safety. The efficacy outcomes are based on the intent-to-treat population (POM+LoDEX, n = 113; POM, n = 108). Results: The median number of prior therapies in each group was 5 (range 1–13). In the POM+LoDEX arm, 30 (27%) pts had high-risk cytogenetics, including del(17p13) and/or t(4p16/14q32). The overall response rate (≥ partial response) was 34% and 15% with POM+LoDEX and POM, respectively, with a median duration of 8.3 (95% CI: 5.8–10.1) and 8.8 (95% CI: 5.5–11.4) mos, respectively. At least minimal response was observed in 45% and 31% of pts, respectively. Median PFS was 4.6 (95% CI: 3.6–5.5) and 2.6 (95% CI: 1.9–2.8) mos with POM+LoDEX and POM, respectively, with a median follow-up of 16.0 and 12.2 mos. Median OS was 16.5 (95% CI: 12.4–18.5) and 13.6 (95% CI: 9.6–18.1) mos, respectively. The most common treatment emergent Gr 3/4 adverse events (AEs) reported in the safety population (n = 219) were neutropenia (44%), anemia (23%), thrombocytopenia (21%), and pneumonia (18%); there were no reports of Gr 3/4 peripheral neuropathy. The incidence of deep-vein thrombosis was low (2%). AEs were managed through dose reductions or interruptions, and supportive care with G-CSF (52%), RBC transfusions (47%), and platelet transfusions (17%). Discontinuations due to AEs were 10%. Conclusions: POM with or without LoDEX is clinically effective and generally well tolerated in RRMM pts who have received multiple prior treatments, including LEN and BORT. AEs were predictable and manageable. Updated data will be presented at the meeting. Clinical trial information: NCT00833833.
Longitudinal whole body MRI (wbMRI) in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma.
Authors: Merz Maximilian , Wagner-Gund Barbara , Neben Kai , Ho Anthony D. , Goldschmidt Hartmut , Hillengass Jens
Published: March 2020

8590

Background: The detection of bone marrow focal lesions (FLs) by MRI at the initial work up has prognostic significance in multiple myeloma (MM), smoldering MM as well as MGUS. Currently, there are no data available on the predictive relevance of new FLs or FLs increasing in size in longitudinally performed wbMRIs for the follow-up of sMM and MGUS. Methods: We retrospectively analyzed 87 patients (sMM n=65; MGUS n=22) that received at least 2 (up to 5) wbMRIs for follow-up. The date of progression into MM requiring systemic therapy was defined as event for the analysis of progression free survival (PFS). Radiological progressive disease (rPD) was defined as the appearance of novel FLs or increase in size of preexisting FLs. Kaplan-Meier plots of PFS for patients with rPD and patients without rPD were analyzed using the log-rank test for significant differences. Results: Median follow-up was 61 months (9.8-101) with a median time between follow-up wbMRIs of 15.8 months (1-73). Progression from sMM/MGUS into MM was found in 28 patients (sMM 40%; MGUS 9%). Using wbMRI, rPD was found in 21 patients (sMM 32%; MGUS 0%). Of all patients, 76% (n=16) with rPD and 16% (n= 9) without rPD progressed into MM during the observation period. Analysis of Kaplan Meyer plots for PFS revealed a highly significant shorter PFS for patients with rPD (32 months) compared to patients with radiological stable disease in wbMRI (PFS not reached; p<0.0001). New appearance or progression of diffuse bone marrow infiltration was not associated with a shorter PFS (not reached; p>0.05). Conclusions: In our study, the appearance of novel FLs or progression of preexisting FLs was highly predictive for progression from sMM into MM requiring systemic treatment. We conclude that wbMRI is effective for the longitudinal follow-up of patients with sMM and MGUS and identifies a group of patients at risk for progression into MM.
Promotion of human multiple myeloma cell growth in vitro and bone marrow invasion in vivo by Notch receptors and the CXCR4/SDF1 axis.
Authors: Chiriva-Internati Maurizio , Mirandola Leonardo , Lazzari Elisa , Colombo Michela , Lancellotti Marialuigia , Cobos Everardo , Yu Yuefei , Figueroa Jose A. , Saadeh Charles , Wade Raymond , Zepeda Kristopher , Mer Jesse , Konala Venu , Radhi Saba , Aulakh Amardeep , Jenkins Marjorie , Jumper Cynthia A. , Alalawi Raed , Chiaramonte Raffaella
Published: March 2020

8591

Background: Multiple myeloma (MM) originates from post-germinal center B cells, and is caused by malignant plasma cells accumulating in the bone marrow. Interactions of MM cells with the bone marrow stroma promote tumor growth, migration and drug resistance. The chemokine receptor CXCR4 and its ligand SDF1 are critical regulators of this process. MM cells frequently hyper-express CXCR4 and respond to SDF1,2 enhancing MM cell infiltration, proliferation and osteolysis. Notch receptors similarly promote MM cell growth, drug resistance and the associated osteolytic process. We hypothesized that the CXCR4/SDF1 axis mediates the effects of Notch signals in MM. Methods: We used real-time PCR, flow-cytometry, E.L.I.S.A. and chemotaxis assay to explore the effects of CXCR4 in cultured human MM cell lines after Notch inhibition or over-stimulation. Additionally, we validated our findings in a NOD/SCID murine model xenografted with human MM cells. Results: Our results show that Notch blocking reduced CXCR4 and SDF1 expression by MM cells. Further, Notch activation was required for MM cell chemotactic and proliferative response to SDF1 in vitro. We then investigated the outcome of anti-Notch treatment on human MM cells bone invasion in NOD/SCID mice. Interfering with Notch activity dramatically reduced xenografted MM cell ability to infiltrate the bone marrow, ultimately resulting in diminished tumor burden. Notably, such effect was associated with a decrease of CXCR4 expression. Conclusions: This was the first time that Notch receptors were reported to regulate the CXCR4/SDF1 axis and bone marrow invasion in human MM. These findings indicate that specific Notch-tailored therapies may effectively hamper CXCR4-mediated bone infiltration and associated lesions, and are expected to significantly improve treatment outcome and survival.
Early versus late treatment for smoldering (asymptomatic) multiple myeloma: A systematic review.
Authors: Alahamdi Mubarak Salem , Tay Jason
Published: March 2020

8593

Background: Expectant management remains the current standard of care for patients with smoldering multiple myeloma (SMM). Recent appreciation of "high risk" smoldering myeloma and the advent of novel therapeutic agents may allow one to better tailor the timing of therapeutic interventions. Herein, we performed a systematic review of the literature, summarizing the available randomized controlled trial (RCT) evidence for treatment of SMM. Methods: Our systematic search strategy includes MEDLINE, EMBASE, Cochrane Database, and relevant bibliographies where the following search concepts were used: RCT, SMM as defined as per the IMW Criteria, and treatment. Two reviewers independently extracted data on study design, population, sample size, treatment, clinical outcomes, and trial quality, were any discrepancies were discussed and resolved. Results: We identified 7 RCTs (2 articles and 5 abstracts) representing 869 patients. Six articles compared early versus deferred treatment for SMM; 2 studies compared early Melphalan plus Prednisone (MP) versus deferred MP. 3 studies compared bisphosphonates versus abstention while one study compared lenalidomide with dexamethasone to therapeutic abstention. Further, one study compared thalidomide with zoledronate to zoledronate alone. The median age is 66. Four studies received a Jadad score of 3 while three studies received a score of 2. Allocation concealment was described in four studies. Risk of disease progression was lower in patients receiving therapy compared to abstention OR 0.5(0.38-0.68). The events that demonstrate disease progression were not clearly defined. Further, the use of combination therapy compared to a single intervention decreased the risk of progression OR 0.23(0.11-0.51). No difference in OS was noted in patients receiving therapy compared to abstention OR 0.95(0.57-1.57). Conclusions: Early treatment of SMM compared with abstention decreases the risk of disease progression. However, OS was not improved by earlier intervention. High risk SMM may benefit from early intervention. The optimal intervention(s) remains to be defined, and further studies are warranted in this understudied population.
Phase I study of TH-302, an investigational hypoxia-targeted drug, and dexamethasone in patients with relapsed/refractory multiple myeloma.
Authors: Ghobrial Irene M. , Laubach Jacob , Armand Philippe , Boswell Erica , Hanlon Courtney , Chuma Stacey , Chu Esther Dawn , Handisides Damian , Kroll Stew , Hickingbottom Barbara , Anderson Kenneth Carl , Richardson Paul Gerard Guy
Published: March 2020

8602

Background: TH-302 is an investigational 2-nitroimidazole prodrug of the DNA alkylator Br-IPM designed to be selectively activated in hypoxia. In multiple myeloma (MM) mouse models, diseased animals demonstrate a marked expansion of areas of hypoxia in the bone marrow. TH-302 exhibited anti-tumor activity against MM in vitro and in vivo and synergism was seen when combined with bortezomib (Hu et al, Blood 2010; Chesi et al, Blood 2012). Based on these findings, a phase I/II study of TH-302 plus dexamethasone (dex) was initiated for patients (pts) with relapsed/refractory MM. Methods: Eligible pts in the study (NCT01522872) had ECOG PS ≤ 2, receipt of at least two prior therapies, and acceptable hepatorenal function and hematologic status. A standard 3+3 dose escalation design was used with a fixed oral 40 mg dose of dex and 40% dose increments of TH-302. TH-302 was administered IV with dex on days 1, 4, 8, and 11 of a 21-day cycle. The objectives were to determine DLTs and the MTD; assess the safety, tolerability and preliminary clinical activity of TH-302 plus dex; and study the relationship between hypoxia within the bone marrow and response to TH-302. Results: Eleven pts have been treated: 7M/4F with a median age 61 years (range: 53 – 86) and 6 prior therapies (range: 3 – 10). All received both bortezomib and lenalidomide/thalidomide containing regimens. TH-302 was dosed at 240 (n=5), 340 (n=4), and 480 (n=2) mg/m² for a median of 5 cycles. No DLTs were reported at 240 or 340 mg/m². Two pts treated at 480 mg/m² had DLTs of grade 3 mucositis, exceeding the definition of MTD. A dose expansion is thus ongoing at 340 mg/m2. Two patients had SAEs related to TH-302 (pneumonia). Five pts continue on study after a median of 7 cycles (range: 2–11). Nine pts have had efficacy evaluations: 2 pts with partial responses, 2 pts with minimal responses, and 5 pts with stable disease, for an overall response rate (of MR or better) of 44%. Conclusions: TH-302 can be administered at 340 mg/m2 biweekly + dex, with dose limiting mucositis seen at higher doses. Initial clinical activity has been noted with an ORR of 44% in heavily pretreated MM pts who are relapsed/refractory to both bortezomib and lenalidomide. Clinical trial information: NCT01522872.