bluuebunny/crossref_metadata_2025 huggingface dataset:
CNS involvement by North American-ATLL (NA-ATLL) is associated with discrete patterns and molecular profile involving XPO1 E571 and KLF2/PI3KCD in selected cases.
Authors: Shah Nishi , Patel Riya Jayesh , Thakkar Astha , Rahman Shafia , Acuna-Villaorduna Ana , Shah Urvi , Herrera Diego Adrianzen , Slasky Shira , Gritsman Kira , Goldfinger Mendel , Kornblum Noah Saul , Shastri Aditi , Mantzaris Ioannis , Bachier-Rodriguez Lizamarie , Braunschweig Ira , Verma Amit , McNeill Katharine Anne , Ye B. Hilda , Janakiram Murali , Sica R. Alejandro ,   BMT/PA Group
Published: May 2020

8063

Background: Information on central nervous system (CNS) involvement with NA-ATLL is limited. In this study, we describe CNS involvement in ATLL patients at a tertiary hospital in New York City. Methods: We considered CNS involvement if one of the following criteria was met 1) cerebrospinal fluid (CSF) cytology or flow cytometry was positive 2) CNS imaging was positive for disease involvement or 3) Physical exam findings were compatible with neurologic involvement. Results: Of 94 NA-ATLL patients, 21 (22.3%) had CNS involvement by ATLL. CSF was involved in 13/21 and 5/21 patients at diagnosis and relapse respectively. At diagnosis, MRI showed CNS involvement in brain and spine in 5/21 (24%) and 3/ 21 (14%) cases respectively. At relapse, imaging revealed brain and spine involvement in 2 patients each. Neurological exam was abnormal in 7 (33%) and 3 (14%) cases at diagnosis and relapse respectively. Next generation exon targeted sequencing was performed in 9 cases. Table shows the mutations (mtn) and functional groups with frequencies. XPO1 E571K mutation was present in 2 patients with extensive CNS disease and refractory to conventional treatment with an overall survival (OS) of 2 months. To our knowledge, this is the first time that XPO1 E571K is reported in a T-Cell malignancy. We also describe here a second set of mutations with CNS involvement (KLF2 and PI3KCD) in 2 patients. Median OS was 8.5 months, Median RFS was 6.5 months in our series. In most cases, the lymphomatous phenotype appeared to have direct mass-like extension (5/21) with several cases of accompanying osteolytic spine or skull lesions, whereas cases with hematogenous involvement tends to spread to the CSF by traversing the brain blood barrier. Conclusions: In this report we describe patterns of CNS involvement in ATLL and the associated mtns. We also describe two unique cases of XPO1E571K mtn in a TCL. [Table: see text]
Safety of acalabrutinib (Acala) monotherapy in hematologic malignancies: Pooled analysis from clinical trials.
Authors: Furman Richard R. , Byrd John C. , Owen Roger G. , O'Brien Susan Mary , Brown Jennifer R. , Hillmen Peter , Stephens Deborah Marie , Patel Priti , Schwartz-Sagi Liat , Baek Marshall , Christian Beth , Dyer Martin J.S. , Streetly Matthew J. , Sun Clare Chui Ling , Rule Simon , Wang Michael , Ghia Paolo , Jurczak Wojciech , Pagel John M. , Sharman Jeff P.
Published: May 2020

8064

Background: Acala is a next-generation, highly selective, covalent Bruton tyrosine kinase inhibitor approved in the US for patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and previously treated mantle cell lymphoma (MCL). We evaluated the safety profile of acala monotherapy (monotx) in multiple B cell malignancies. Methods: Data from pts with activated B-cell diffuse large B-cell lymphoma, CLL, follicular lymphoma, MCL, multiple myeloma, prolymphocytic leukemia, Richter syndrome, SLL, or Waldenström macroglobulinemia treated with ≥1 dose of acala monotx in 9 studies were pooled. Acala was administered at 100 mg BID in most pts (100–400 mg total dose daily). Adverse events (AE) were assessed. Results: A total of 1040 pts were included (median age: 67 y [range: 32–90]; ECOG status ≤1: 93%; median exposure duration: 24.6 mo [range: 0–58.5]). A total of 360 (34%) pts discontinued acala, most commonly due to progressive disease (PD; 17%). AEs led to acala discontinuation in 97 (9%) pts; those in > 2 pts were pneumonia (n = 5) and thrombocytopenia (n = 4). Incidence of AEs, including the most common (any grade and grade ≥3), are shown in the Table. Events of clinical interest (ECIs) included atrial fibrillation (afib) of any grade in 46 (4%) pts and grade ≥3 in 13 (1%) pts; major hemorrhage (any grade) in 37 (4%) pts; grade ≥3 infection in 183 (18%) pts; hypertension (any grade) in 79 (8%) pts and grade ≥3 in 36 (4%) pts; and second primary malignancies (SPM) excluding non-melanoma skin cancer (NMSC; any grade) in 68 (7%) pts. Median (range) time to first onset in days for each ECI (any grade) was: afib, 522 (8–1280); major hemorrhage, 293 (4–1327); infections, 92 (1–1317); hypertension, 157 (2–1345); SPM excluding NMSC, 339 (7–1499). Death was reported in 139 (13%) pts, most commonly due to PD (6%) and AEs (5%). Conclusions: Acala monotx has a favorable tolerability profile with increased exposure across multiple mature B cell malignancies. Additional analyses will further explore the longitudinal characteristics of AEs. [Table: see text]
A phase I/II study to assess safety and dose of ixazomib in combination with cyclophosphamide and dexamethasone in newly diagnosed patients with light chain (AL) amyloidosis.
Authors: Osman Keren
Published: May 2020

8065

Background: AL amyloidosis is an incurable clonal plasma cell disorder characterized by tissue deposits of immunoglobulin light chain fragments leading to organ dysfunction and death. Standard treatment for newly diagnosed patients (pts) has traditionally included oral melphalan + dexamethasone as well as high-dose melphalan + ASCT. Here we report preliminary results of a Phase 1/2, open-label, multi-institution study of ixazomib (I) in combination with cyclophosphamide (Cy) and dexamethasone (D) in newly diagnosed AL amyloidosis. Methods: Eligible pts are ≥18 years with newly diagnosed, untreated biopsy-proven AL amyloidosis. A total of up to 30 pts will be enrolled, with up to 18 in the dose escalation arm (phase 1) and 12 in the maximum tolerated dose (MTD) expansion arm (phase 2) according to a classical 3+3 design. Four dose levels were evaluated in phase 1. I and Cy are given orally (PO) on days 1, 8, 15, and D 20mg PO on days 1, 8, 15, 22 of each 28-day cycle. Treatment continues for a total of 6 cycles or until disease progression, significant toxicity or withdrawal. The primary study objective in phase 1 is to establish the MTD and in phase 2 is to determine hematologic/organ response rate. Results: As of February 2020, 120 pts have been enrolled; 16 in phase 1 and 4 in phase 2. The MTD was established at dose level 3 (I 4mg and Cy 500mg). Median age is 65 years (range 46-79), 12 (67%) are male. Light chain isotype is lambda in 14 (78%). Seven pts (39%) have cardiac, 10 (56%) renal, 4 (22%) gastrointestinal, 1 (6%) hepatic, 2 (11%) soft tissue involvement, with 22% having multi-organ involvement. Four pts (22%) completed 6 cycles of therapy and 6 (33%) remain on study with a median of 3 cycles completed. Eight of 16 pts (50%) had at least 1 drug-related adverse event (AE) (any grade), most commonly edema (19%), fatigue (19%), dizziness/lightheadedness (13%) and lymphopenia (13%). Grade 3/4 AEs were rare with grade 3 lymphopenia, anemia, and hyponatremia occurring in 13%, 6%, and 6% of pts, respectively. Of 18 evaluable pts, 7 (39%) achieved ≥VGPR with the median time to best response 2 cycles (1-5). Conclusions: The combination of ICyD for pts with newly diagnosed AL amyloidosis is safe and well tolerated. Phase 1 is completed and the recommended phase 2 dose has been established. Deep hematologic responses (≥VGPR) have occurred and time to response appears similar to standard of care induction regimens, ie CyBorD. Phase 2 response data will be updated at the meeting.
First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).
Authors: Richardson Paul G. , Vangsted Annette J. , Ramasamy Karthik , Trudel Suzanne , Martínez Joaquín , Mateos Maria-Victoria , Rodríguez Otero Paula , Lonial Sagar , Popat Rakesh , Oriol Albert , Karanes Chatchada , Orlowski Robert Z. , Berdeja Jesus G. , Wong Lilly , Shi Chenyang , Lamba Manisha , Barnett Evelyn , Pierce Daniel W. , Pourdehnad Michael , Bahlis Nizar J.
Published: May 2020

8500

Background: CC-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed for rapid, maximal degradation of Ikaros and Aiolos. In vitro, it has enhanced antiproliferative and tumoricidal activity in MM cell lines, including those resistant to lenalidomide (LEN) and pomalidomide (POM), with strong immune stimulatory activity. Methods: A phase 1, multicenter, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose, safety, tolerability, and pharmacokinetics of CC-92480 + DEX in heavily pretreated RRMM pts. Eligible pts had progression on or within 60 days of their last MM therapy and were either resistant or intolerant to, or not otherwise candidates for currently available therapies. Several treatment schedules tested escalating doses of CC-92480 + DEX (40 mg; 20 mg if ≥75 yrs). Results: As of Dec 24, 2019, 66 pts had received CC-92480 + DEX. Median age was 67 yrs (range 40–78), median number of prior regimens was 6 (range 2–13). Prior therapies included stem cell transplantation (67%), bortezomib (92%), LEN (89%), POM (83%), and anti-CD38 antibodies (78%). CC-92480 doses explored included 0.1–1.0 mg QD (10/14 days × 2), 0.8–1.0 mg QD (21/28 days), 0.2–0.8 mg BID (3/14 days × 2), and 1.6–2.0 mg QD (7/14 days × 2). MTD was 1.0 mg for both 10/14 × 2 and 21/28 schedules. Grade 3–4 treatment-emergent adverse events (TEAEs) were reported in 58 (88%) pts. Most frequent grade 3–4 TEAEs included neutropenia (53%), infections (30%), anemia (29%), and thrombocytopenia (17%), with 9% grade 3 fatigue. Among different cohorts,10 pts had dose-limiting toxicities (the majority related to neutropenia). Overall response rate (ORR) was 21% (9 very good partial responses [VGPRs]; 5 PRs) for efficacy evaluable population (n = 66). Efficacy was dose and schedule dependent; across two 1.0 mg QD schedules (10/14 × 2 and 21/28), 10 of 21 (48%) pts responded (7 VGPR and 3 PR), with response independent of immunomodulatory drug (IMiD) refractoriness. Plasma exposure increase and peripheral blood Ikaros and Aiolos degradation were dose dependent. Ikaros and Aiolos significantly decreased in bone marrow plasma cells of LEN- and POM-refractory pts. Conclusions: TEAEs of CC-92480 were mainly related to myelosuppression in heavily pretreated, including triple-class-refractory, RRMM pts. Promising activity with 48% ORR at therapeutic doses was observed. The study is ongoing to further optimize dose and schedule, with combination studies underway and dose expansion cohorts planned. Clinical trial information: NCT03374085 .
Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011).
Authors: Mailankody Sham , Jakubowiak Andrzej J. , Htut Myo , Costa Luciano J. , Lee Kelvin , Ganguly Siddhartha , Kaufman Jonathan L. , Siegel David Samuel DiCapua , Bensinger William , Cota Mariana , Doerr Thomas , DeVries Todd , Wong Sandy Wai Kuan
Published: May 2020

8504

Background: Orva-cel is an investigational, BCMA-directed CAR T cell product with a fully human binder. Over 100 pts have been treated in the EVOLVE phase 1 study. Pts treated at 50 and 150 × 106 CAR+ T cells were previously reported (Mailankody ASH 2018 #957). We now report results of the higher dose levels (DLs) in 51 pts who received orva-cel manufactured using the process intended to support commercial use. Methods: Pts with RRMM who had ≥3 prior regimens, a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (mAb), received orva-cel at 300, 450, and 600 × 106 CAR+ T cells after lymphodepletion with fludarabine/cyclophosphamide. Results: Median pt age was 61 (range, 33–77) y; median time from diagnosis was 7.0 (range, 1.7–23.6) y, with a median of 6 (range, 3–18) prior regimens. Overall, 92% of pts were penta-exposed (2 IMiDs, 2 PIs, and an mAb); 61% of pts received bridging therapy (77% were refractory to bridging therapy). Two pts had dose-limiting toxicities: grade 3 neurological event (NE) for >7 d at 300 × 106 CAR+ T cells and grade 4 neutropenia for >28 d at 450 × 106 CAR+ T cells. Key efficacy and safety outcomes are shown in the Table. Cytokine release syndrome (CRS)/NEs were managed with tocilizumab and/or steroids (78%), anakinra (14%), and/or vasopressors (6%). Grade ≥3 anemia, neutropenia, and thrombocytopenia at 29 d occurred in 21%, 55%, and 44% of pts (median time to resolution to grade ≤2 of any cytopenia, ≤2.1 mo). Grade ≥3 infections occurred in 14%. After a median follow-up (F/U) of 5.9 mo, median progression-free survival was not reached. Conclusions: Orva-cel at 300, 450, and 600 × 106 CAR+ T cells demonstrated manageable safety (CRS grade ≥3: 2%; NE grade ≥3: 4%) and compelling efficacy in heavily pretreated pts with RRMM, with a 91% objective response rate (ORR) and 39% complete response (CR)/stringent CR (sCR) rate. Updated results will be presented, including minimal residual disease, durability of response, and recommended phase 2 dose. Clinical trial information: NCT03430011 . [Table: see text]
Depth of response to isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: Interim analysis of the GMMG-CONCEPT trial.
Authors: Weisel Katja , Asemissen Anne Marie , Besemer Britta , Haenel Mathias , Blau Igor W. , Goerner Martin , Ko Yon-Dschun , Dürig Jan , Staib Peter , Mann Christoph , Lutz Raphael , Munder Markus , Graeven Ullrich , Peceny Rudolph , Salwender Hans , Zago Manola , Benner Axel , Tichy Diana , Bokemeyer Carsten , Goldschmidt Hartmut
Published: May 2020

8508

Background: High-risk (HR) multiple myeloma (MM) still has a significant impaired prognostic outcome. Addition of CD38 monoclonal antibodies to standard-of-care regimens significantly improved response rates and depth of response in newly diagnosed (ND) and relapsed/refractory MM patients (pts). Here, we report the prespecified end of induction interim analysis (IA) of the investigator-initiated GMMG-CONCEPT trial (NCT03104842), evaluating the quadruplet regimen isatuximab plus carfilzomib, lenalidomide and dexamethasone (Isa-KRd) in HR NDMM pts. Methods: 153 pts with HR NDMM are planned to be included into the trial. HR MM is defined by the presence of del17p or t(4;14) or t(14;16) or > 3 copies 1q21 and ISS 2 or 3 stage disease. Pts receive 6 cycles of Isa-KRd induction, 4 cycles of Isa-KRd consolidation and Isa-KR maintenance. Transplant eligible pts (arm A) undergo high-dose therapy. Transplant ineligible pts (arm B) receive 2 additional cycles of Isa-KRd induction. The primary endpoint is MRD negativity measured by next-generation flow after consolidation. This IA reports on overall response rates (ORR) after induction. Additional MRD analysis will be presented. Results: 50 pts (46 arm A, 4 arm B) were included in the IA population for ORR. HR MM was defined by del17p in 52%, t(4;14) in 38%, t(14;16) in 12% and > 3 copies 1q21 in 42%. 39/46 pts in arm A and 4/4 pts in arm B completed induction treatment. ORR was 100%, with 5 pts (10.0%) showing partial response (PR), 22 (44.0%; including 4 in arm B) very good partial response (VGPR) and 23 (46.0 %) complete response (CR). Median stem cell yield was 6.6 × 106CD34+ cells/kg. Grade 3/4 treatment-emergent adverse events (≥ 10%) with Isa-KRd included neutropenia (34.0%), leukopenia (26.0%) and thrombocytopenia (14.0%). Main non-hematologic toxicities grade 3/4 were hypertension (12.0%) and infection (8.0%). Conclusions: To the best of our knowledge, we report for the first time on a trial investigating solely HR NDMM and Isa-KRd quadruplet treatment. Isa-KRd induction induces deep responses in HR MM pts. The overall safety profile of Isa-KRd is expected and consistent with previous reports. The study is ongoing, with pts continuing to be included. Clinical trial information: 03104842 .
A first-in-class ex vivo combination between cytokine-induced memory like (CIML) NK cells and a CD38 targeting antibody recruiting molecule (ARM) as a novel approach to target NK cells without cellular engineering for the treatment of multiple myeloma.
Authors: Rastelli Luca , Mohsin Maqbool , Rossi Ann Marie , Alvarez Sotomayor Enrique , Iben Lawrence , Vaill Ada , Welsch Matthew , Romee Rizwan , Bunin Anna
Published: May 2020

8523

Background: Cytokine-induced memory-like (CIML) NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for several weeks to months. Antibody Recruiting Molecules (ARM) are bifunctional molecules that simultaneously bind a given tumor marker and engage endogenous IgG antibodies, therefore binding and activating NK cells via their FcR and targeting them to kill tumors cells. A first in class therapy that has the potential to improve the activity of CIML NK cells by combining them with KP1237, a CD38-ARM is presented for the treatment of newly diagnosed multiple myeloma (MM) patients who are minimal residual disease positive (MRD+) and eligible for autologous stem cell transplant (ASCT). Methods: Specific killing of CD38 expressing MOLP-8 cells by CIML NK cells alone or in combination with KP1237 was measured. Additionally, NK and CIML NK cells from healthy volunteers and MM patients at various stages of the disease were tested for activity against autologous and allogeneic tumor cell targets. In these experiments, surface phenotype and activation status of NK cells were determined. Results: A statistically significant increase in specific killing was observed when KP1237 was used in combination with CIML NK cells in an ADCC assay against CD38 expressing MOLP-8 (p = 0.0105, mean 61.8 ± SD 9.1 and mean 83.7 ± SD 13.58 for CIML NK alone and CIML NK+KP1237, respectively). This effect was accompanied by an increase in plasma membrane retention of CD107a. Surface phenotype of NK and CIML NK cells from healthy volunteers and MM patients was compared since the functional activity of NK cells from such patients is debated. We report surface expression of CD56, CD16, CD57, NKG2D, Nkp44, Nkp46, CD107a, KIR2DL2/3/DS2, and CD69 as well as frequencies of CD57hi CD56+ mature versus CD57lo CD56+ immature NK cell subsets. Further, autologous CIML NK cells + KP1237 exhibit cytotoxicity towards patient plasma cells. Conclusions: The activity of CIML NK cells towards CD38 expressing MM target cells is improved by the addition of KP1237 avoiding the need for cellular engineering with chimeric antigen receptors. This led to the development of the combination drug product consisting of patient autologous CIML NK cells, KP1237 and IVIG. Clinical development is under way for (MRD+) MM patients eligible for ASCT.
KarMMa-RW: A study of real-world treatment patterns in heavily pretreated patients with relapsed and refractory multiple myeloma (RRMM) and comparison of outcomes to KarMMa.
Authors: Jagannath Sundar , Lin Yi , Goldschmidt Hartmut , Reece Donna Ellen , Nooka Ajay K. , Rodríguez Otero Paula , Matsue Kosei , Shah Nina , Anderson, Jr Larry D. , Wilson Kimberly , Swern Arlene S. , Zafar Faiza , Agarwal Amit Balkrishna , Siegel David Samuel DiCapua
Published: May 2020

8525

Background: RRMM patients (pts) triple-class exposed (to immunomodulatory drugs [IMiDs], proteasome inhibitors [PIs] and anti-CD38 monoclonal antibodies [mAbs]) have limited treatment (tx) options. The ongoing phase II KarMMa study (NCT03361748) is examining idecabtagene vicleucel (ide-cel; bb2121), a BCMA targeted CAR T cell therapy, in RRMM pts with ≥3 prior regimens (IMiD, PI and CD38 mAb inclusive) who are refractory to their last tx per IMWG criteria. This study aimed to 1) assess tx patterns and outcomes in real world (RW) RRMM pts similar to the KarMMa population and; 2) compare outcomes with SoC in a synthetic cohort vs ide-cel in KarMMa. Methods: In this global, noninterventional, retrospective study (KarMMa-RW), pt-level data from clinical sites, registries and databases were collated into a single data model. RW pts meeting KarMMa eligibility criteria (eligible cohort; EC) were compared with KarMMa (N = 128) using trimmed stabilized inverse probability of tx weighted propensity scores (IPTW PS) for pts in both studies with Poisson regression for ORR and ≥VGPR, and Cox models with study as a term for PFS. All models were adjusted for unbalanced covariates. Results: Of 1949 RW pts, 1171 were refractory to last regimen (median age, 68 y; median no. of prior regimens, 5; triple-class refractory, 41%). Further selection for subsequent tx, organ function and no comorbidities yielded 190 EC pts who had > 90 distinct tx regimens. With a median follow-up of 11.3 mo (KarMMa) and 10.2 mo (EC) at data cutoff (Oct 30, 2019), ORR, ≥VGPR and PFS were significantly improved in KarMMa vs EC (Table). Conclusions: Results from the KarMMa-RW study confirm that there is no clear SoC for heavily pretreated RW RRMM pts and responses are suboptimal with currently available therapies. Ide-cel showed deep, durable responses and significantly improved PFS in RRMM pts, representing a potential new tx option in RRMM. Clinical trial information: tbd . [Table: see text]
Diagnostic performance of skeletal survey versus 18F-FDG-PET/CT for detecting lytic lesions in smoldering multiple myeloma.
Authors: Hill Elizabeth M. , Dew Alexander , Morrison Candis , Choyke Peter L. , Mena Esther , Lindenberg Liza , Kazandjian Dickran Garo
Published: May 2020

8532

Background: Per NCCN Guidelines for smoldering multiple myeloma (SMM), whole body radiography, i.e. skeletal survey (SS), should be used to rule out osteolytic bone lesions. If negative, more sensitive imaging techniques such as whole body 18F-FDG-PET/CT(PET/CT), MRI, or low dose CT should be used to differentiate between SMM and multiple myeloma (MM). The false-negative rate of SS is high (30-70%). The frequency of false-positive SS in SMM is less well known but important because of its common use in community practice. We examine the specificity of SS in patients with a presumed diagnosis of SMM and question if SS is still warranted prior to modern imaging techniques to confirm a diagnosis of SMM. Methods: Records of patients sequentially referred from the community and evaluated for a presumed diagnosis of SMM at the National Institutes of Health Myeloma Program between April 2010 to January 2020 were reviewed. Patients with a SS and PET/CT performed within 30 days were included. Positive findings on PET/CT were defined per the 2014 IMWG criteria as one or more sites of osteolytic bone destruction seen on CT. The sensitivity and specificity of SS were calculated using PET/CT as the reference test. Results: Charts from 144 patients with presumed SMM were reviewed. A total of 76 SMM patients had both a SS and PET/CT performed within 30 days of each other. Sixty-four patients (84.2%) showed concordant results. Twelve (15.8%) patients had discordant imaging results. SS was falsely negative in 3 (4.7% (95% CI: 1.2%-14.2%)) patients and falsely positive in 9 (69.2% (95% CI: 38.9%-89.6%)) patients. SS had a sensitivity of 57.1% (95% CI: 20.2%-88.2%) and a specificity of 86.9% (95% CI: 76.2-93.5). Conclusions: In patients presumed to have SMM, disease burden is low thus highly sensitive imaging modalities are needed to rule out bone disease. This study confirms the low sensitivity of SS in the SMM population. It more importantly points out the low specificity of SS in SMM. The IMWG no longer recommends conventional SS prior to whole body CT (or PET/CT) as first imaging choice in SMM. While the argument may be made that SS should still be used upfront due to low cost and widespread availability, this study shows the risk of overestimating disease. Over 10% of patients in this series had false positive disease on SS and thus at risk of receiving unnecessary treatment. Not only concerning for patient toxicity but more so financial toxicity. If SS is used, it is important to review positive findings directly with a radiologist and consider follow-up confirmatory imaging.
Association of elevated red cell distribution width and overall survival in multiple myeloma.
Authors: Rubinstein Sam , Sigworth Elizabeth , Chen Qingxia M , Chaugai Sandip , Cornell Robert F. , Warner Jeremy Lyle
Published: May 2020

8534

Background: The most widely used multiple myeloma (MM) staging system, the Revised International Staging System (R-ISS), is based on lactate dehydrogenase, albumin, cytogenetics, and beta-2 microglobulin (B2M). B2M has limited clinical utility, is often only obtained to compute R-ISS, and is often a send-out test. Prior studies have shown that elevated red cell distribution width (RDW), a common test that is part of the routine complete blood count, is associated with reduced overall survival (OS) in MM. We hypothesized that a MM staging system could be constructed replacing B2M with RDW. Methods: Patients treated at Vanderbilt University Medical Center from 2000 to 2018 with cancer registry-confirmed MM diagnoses were included. OS was computed by registry-curated death and diagnosis dates; living patients were censored at date last known alive or of last follow up. A Cox proportional hazards model determining the independent effects of R-ISS, age, and RDW on OS was built. An alternate staging system (RDW-SS) was developed, replacing the B2M cutoffs in R-ISS with RDW (stage 1: RDW < 14.0% stage 2: RDW 14.0-15.5%; stage 3: RDW > 15.5%). Cox models comparing RDW-SS and R-ISS after adjustment for age and category of induction therapy (proteasome inhibitor [PI] and immunomodulatory drug [IMiD]), PI only, IMiD only, other) were built. Results: In 604 MM patients with available data, RDW was independently associated with OS after adjustment (HR = 1.069 per 1% RDW increase, p < 0.001). RDW-SS stages were associated with reduced OS (RDW-SS 2 HR 1.52, 95% CI 1.09 – 2.11, p = 0.01; RDW-SS 3 HR 2.13, 95% CI 1.37 – 3.28, p < 0.001) after adjustment; R-ISS stages were not (Table). Conclusions: RDW at MM diagnosis was independently associated with reduced OS, after adjustment for the clinical factors of age and treatment exposure; notably, R-ISS was not. The RDW-SS is simpler to obtain than R-ISS and may have improved prognostic value pending independent validation. If confirmed, mechanistic study of the etiology of this relationship is warranted. [Table: see text]
Pivotal DREAMM-2 study: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) refractory to proteasome inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mAbs).
Authors: Lonial Sagar , Lee Hans Chulhee , Badros Ashraf , Trudel Suzanne , Nooka Ajay K. , Chari Ajai , Abdallah Al-Ola A. , Callander Natalie Scott , Sborov Douglas Weston , Suvannasankha Attaya , Weisel Katja , Voorhees Peter Michael , Hoos Axel , Zhi Eric , Baron January , Piontek Trisha , Jewell Roxanne C. , Opalinska Joanna , Gupta Ira , Cohen Adam D.
Published: May 2020

8536

Background: Single-agent belantamab mafodotin (B-cell maturation antigen targeting immunoconjugate) showed clinically meaningful activity and manageable safety in patients with heavily pre-treated RRMM (DREAMM-2, NCT03525678, Lancet Oncol.2020). We report updated results (median follow-up 9 months). Methods: DREAMM-2 is an ongoing single-agent belantamab mafodotin (2.5 or 3.4 mg/kg) study in patients with RRMM after ≥3 prior therapy lines and refractory to an immunomodulatory agent, a PI, and refractory and/or intolerant to an anti-CD38 mAb. Primary endpoint: overall response rate (ORR; ≥partial response per independent review committee). Results: ORR was 31% in the 2.5 mg/kg (19% with ≥very good partial responses [VGPR]) and 35% (24% with ≥VGPR) in the 3.4 mg/kg groups (Table). Duration of response (DoR) was not reached (NR) in the 2.5 mg/kg and 6.2 months in the 3.4 mg/kg groups; 1-year overall survival (OS) estimate was 53%. Common Grade 3/4 AEs ( > 10% in either group) were keratopathy (2.5: 29%; 3.5: 24%), thrombocytopenia (2.5: 21%; 3.4: 32%), anemia (2.5: 20%; 3.4: 27%), pneumonia (2.5: 6%; 3.4: 13%), and neutropenia (2.5: 11%; 3.4: 16%). AEs were managed with dose delays (2.5: 54%; 3.4: 62%) and reductions (2.5: 34%; 3.4: 43%); discontinuations due to AEs were uncommon (2.5: 9%; 3.4: 12%). Conclusions: Single-agent belantamab mafodotin was well-tolerated, and clinically meaningful responses were sustained despite dose modifications with longer follow-up. Funding: GlaxoSmithKline (205678). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03525678 . [Table: see text]
Daratumumab + bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM): Baseline SLiM-CRAB based subgroup analysis of CASSIOPEIA.
Authors: Touzeau Cyrille , Moreau Philippe , Perrot Aurore , Hulin Cyrille , Dib Mamoun , Tiab Mourad , Caillot Denis , Facon Thierry , Leleu Xavier , van de Donk Niels W.C.J. , Broijl Annemiek , Zweegman Sonja , Levin Mark-David , Delforge Michel , Pei Lixia , Vanquickelberghe Veronique , De Boer Carla , Kampfenkel Tobias , Vermeulen Jessica , Sonneveld Pieter ,   on behalf of IFM and HOVON
Published: May 2020

8538

Background: In the phase 3 CASSIOPEIA study, D-VTd significantly improved outcomes vs VTd in TE NDMM pts at an 18.8-mo median follow-up. To allow earlier diagnosis and treatment of MM, the IMWG added 3 validated biomarkers (≥60% clonal bone marrow plasma cells, serum free light chain ratio ≥100, and > 1 focal bone lesion by MRI; “slim”) to the conventional “CRAB” diagnostic criteria. We present a subgroup analysis of CASSIOPEIA based on baseline slimCRAB criteria. Methods: TE NDMM pts were randomized 1:1 to 4 pre-ASCT induction and 2 post-ASCT consolidation cycles of D-VTd or VTd. The “slim-only” subgroup excludes pts with ≥1 conventional CRAB criterion based on data collected at baseline; the remaining pts were included in the “CRAB” subgroup. Results: Of 1085 randomized pts (543 D-VTd; 542 VTd), 81 were included in the slim-only subgroup (36 D-VTd; 45 VTd) and 1004 were included in the CRAB subgroup. In slim-only vs CRAB pts, 22% vs 54% had an ECOG score of ≥1, 4% vs 16% had ISS Stage III disease, and 11% vs 16% had high-risk cytogenetics. For D-VTd vs VTd pts in the slim-only group, these rates were 22% vs 22%, 8% vs 0%, and 6% vs 16%, respectively. Overall response rates (ORR) and rates of sCR, ≥CR, and MRD negativity were similar between slim-only and CRAB pts; for slim-only pts, rates were significantly higher for D-VTd vs VTd (Table). After an 18.8-mo median follow-up, progression-free survival (PFS) was not significantly different in slim-only vs CRAB pts, or in D-VTd vs VTd slim-only pts (Table). For D-VTd vs VTd CRAB pts, 18-mo PFS rates were 92% vs 84%, and 24-mo PFS rates were 89% vs 76%. Conclusions: Baseline characteristics indicate that slim-only pts were slightly fitter and of lower risk status vs CRAB pts; however, response rates, MRD-negativity rates, and PFS did not differ significantly between these groups. Among slim-only pts, significantly higher response and MRD-negativity rates were achieved with D-VTd vs VTd. Among CRAB pts, PFS rates were higher with D-VTd vs VTd. Clinical trial information: NCT02541383 . [Table: see text]
Efficacy of daratumumab in the treatment of multiple myeloma with high-risk cytogenetics: Meta-analysis of randomized phase III trials.
Authors: Giri Smith , Grimshaw Alyssa , Bal Susan , Godby Kelly Nicole , Kharel Prakash , Djulbegovic Benjamin , Usmani Saad Zafar , Facon Thierry , Moreau Philippe , Dimopoulos Meletios A. , Mateos Maria-Victoria , Costa Luciano J.
Published: May 2020

8540

Background: The addition of Daratumumab (D) to backbone multiple myeloma (MM) regimens leads to improved response rates and progression free survival (PFS). Whether improved outcomes are also seen among patients with high-risk cytogenetics (HRC) remains unclear, particularly in first-line (FL) setting. Methods: We conducted a systematic search of bibliographic databases, clinical trials registries and meeting libraries from inception to December 2019, for phase III randomized trials that compared backbone MM regimens vs. same regimen plus D either in FL or relapsed/refractory (R/R) setting and reported outcomes by cytogenetic risk (HRC vs standard risk cytogenetics, SRC). We defined HRC as presence of t(4;14), t(14;16) or del(17p). The primary endpoint was PFS. We pooled relative log-hazard ratios using DerSimonian-Laird random-effects model. We assessed heterogeneity using Cochran’s Q and the I2 statistic. Results: Of 3,070 studies screened, 6 phase III trials were included. This included 3 trials in FL setting (Alcyone, Maia and Cassiopeia, 2,528 patients, 358 HRC) and 3 trials in R/R setting (Castor, Pollux and Candor, 1,533 patients, 222 HRC). The addition of D to FL backbone regimens among patients with HRC led to improved PFS (pooled HR 0.67; 95% CI 0.47-0.95, p = 0.02) with little heterogeneity (Cochran’s Q p = 0.77, I2= 0), similar to R/R setting (pooled HR 0.45; 95% CI 0.30-0.67, p < 0.01, Cochran’s Q = 0.63, p < 0.01, I2= 0). Similar results were seen in SRC MM patients in FL setting (pooled HR 0.45; 95% CI 0.37-0.54, p < 0.01, Cochran’s Q p = 0.49, I2= 0) and R/R setting (pooled HR 0.38; 95% CI 0.25-0.56; p < 0.01, Cochran’s Q p = 0.04, I2= 70%). Conclusions: Incorporating D to backbone regimens led to improved PFS among patients with HRC MM in both FL and R/R setting. Lack of substantial heterogeneity suggests benefit of D regardless of backbone regimen. D based regimens are appropriate choices in FL and R/R setting for both SRC and HRC patients. Longer follow up with mature overall survival data is needed to validate these findings. [Table: see text]
CTONG1104: Adjuvant gefitinib versus chemotherapy for resected N1-N2 NSCLC with EGFR mutation—Final overall survival analysis of the randomized phase III trial 1 analysis of the randomized phase III trial.
Authors: Wu Yi-Long , Zhong Wenzhao , Wang Qun , Mao Weimin , Xu Song-Tao , Wu Lin , Chen Chun , Cheng Ying , Xu Lin , Wang Jun , Li Xiao-Fei , Li Jian , Huang Cheng , Liu Zhidong , Xu Shun , Yang Jin-Ji , Yan Hong-Hong , Yang Xue-Ning , Liu Si-yang , Zhou Qing
Published: May 2020

9005

Background: ADJUVANT-CTONG1104, a randomized phase 3 trial showed adjuvant gefitinib treatment significantly improved disease-free survival (DFS) vs standard doublet chemotherapy in patients (pts) with epidermal growth factor receptor ( EGFR) mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC). 5-year survival rate of N1N2 were 38%-50% in IASLC staging system. Here, we present the final overall survival (OS) results from the study. Methods: From Sep 2011 to April 2014, 222 patients, aged 18-75 years, with EGFR activating mutation through completely resection and diagnosed as stage II-IIIA (N1-N2) NSCLC pathologically from 27 sites were enrolled. The enrolled patients were 1:1 randomized to receive adjuvant gefitinib (250 mg once per day) for 24 months (G, n=111) or vinorelbine (25 mg/m2, d1 and d8) plus cisplatin (75 mg/m2, d1) every 3 weeks for 4 cycles (C, n=111). The primary endpoint was DFS in the ITT population. Secondary endpoints included OS, 3 and 5-year DFS rate, 5-year OS rate. The subsequent therapy data were collected, including crossover from C to G, re-challenge TKI and other treatment. Data cut-off date was Jan. 13, 2020. Results: A median follow-up was 76.9 months. The median OS (mOS) was 75.5 months based on 95 (42.8%) events in ITT whole population. The mOS was 75.5m in G arm and 79.2m in C arm (HR 0.96, 95%CI 0.64-1.43, p=0.823). The 3, 5-year OS rate were 68.6%, 53.8% in G and 67.5%, 52.4% in C respectively. DFS in 3, 5-y were 40.3%, 23.4% in G and 33.2%, 23.7% in C, respectively (P3-y=0.395, P5-y=891). All predefined subgroups including age, gender, lymph node, EGFR mutation type had no significant difference in statistics but in favor of G arm in trend. Subsequent treatment especially targeted therapy contributed most to OS (HR = 0.46, 95% CI 0.26 – 0.83). Median OS of patients receiving subsequent target therapy was75.5m (n=35), 36.4m in other treatment (n=33; (P<0.001). For G mOS were 75.5 (n=15; target therapy) and 35.0 (n=18; other, p<0.001), for C 62.8m (n=20) and 46.8m (n=15; p=0.251). The RR was 26.7%, DCR 66.7%, mPFS 14.1m and mOS 19.6m for patients with rechallenged EGFR TKI in G arm (n=15). No novel unexpected SAE was observed during follow up. Conclusion The DFS survival advantage did not translate to OS difference in ADJUVANT trial. The OS with 75.5m was the best one of survival in completely resected N1N2 NSCLC comparing with historical data and sequent TKI treatment contribute to overall survival. Clinical trial information: NCT01405079.
Randomized phase III study of irinotecan/cisplatin (IP) versus etoposide/cisplatin (EP) for completely resected high-grade neuroendocrine carcinoma (HGNEC) of the lung: JCOG1205/1206.
Authors: Kenmotsu Hirotsugu , Niho Seiji , Tsuboi Masahiro , Wakabayashi Masashi , Ishii Genichiro , Nakagawa Kazuo , Daga Haruko , Tanaka Hiroshi , Saito Haruhiro , Aokage Keiju , Takahashi Toshiaki , Menju Toshi , Kasai Takashi , Yoshino Ichiro , Minato Koichi , Okada Morihito , Katayama Hiroshi , Asamura Hisao , Ohe Yuichiro , Watanabe Shun-ichi
Published: May 2020

9006

Background: In the WHO classification, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are considered as high-grade neuroendocrine carcinoma (HGNEC) of the lung. Although there were no randomized trials evaluating adjuvant chemotherapy for patients (pts) with resected HGNEC, EP was considered to be a standard regimen for this population. A phase III study showed the superiority of IP to EP in pts with extensive stage SCLC (JCOG9511). Methods: Pts with completely resected HGNEC were randomized in a 1:1 ratio to receive either etoposide (100 mg/m2, days 1-3)/cisplatin (80 mg/m2, day 1) or irinotecan (60 mg/m2, days 1, 8, 15)/cisplatin (60 mg/m2, day 1), using the minimization method according to sex, pathologic stage, histology and institution. The primary endpoint was changed from overall survival (OS) to relapse-free survival (RFS) during the study period. We assumed a 3-year RFS of 59% of EP arm and 72% of IP arm (hazard ratio (HR) of 0.623). Planned sample size was 220 in total to give a power of 80% with a one-sided alpha of 5%, an accrual period of 6 years and a follow-up period of 3 years. Results: Between April 2013 and October 2018, 221 pts with a median age of 66 years, pathological stage I (54%), SCLC (53%), were randomly assigned to the EP arm (n = 111) or the IP arm (n = 110). In the second interim analysis, the predictive probability that IP would be superior to EP at the time of the primary analysis was 15.9%, which led to early termination of the trial. With a median follow-up of 24.1 months, 3-year RFS was 65.4% versus 69.0% with HR of 1.076 (95% CI, 0.666-1.738; log-rank test, one-sided P= 0.619). In the subgroup analyses of histology, 3-year RFS in SCLC was 65.2% versus 66.5% with HR of 1.029 (95% CI, 0.544-1.944), and 3-year RFS in LCNEC was 66.5% versus 72.0% with HR of 1.072 (95% CI, 0.517-2.222). Overall survival at 3 years was 84.1% versus 79.0% with HR of 1.539 (95% CI, 0.760-3.117). Proportions of treatment completion were 87.4% (EP) and 72.7% (IP). Incidences (EP/IP) of grade 3 or 4 febrile neutropenia (20.2/3.7%) or neutropenia (97.2/35.8%) were more common in EP. Grade 3 or 4 diarrhea (0.9/8.3%) or anorexia (6.4/11.1%) were more common in IP. One treatment-related death due to tracheal bleeding was observed in IP. Conclusions: This study failed to show the superiority of IP to EP in RFS for pts with completely resected HGNEC. EP is still a standard treatment for this population. Clinical trial information: UMIN000010298.
A phase I safety and feasibility study of neoadjuvant chemoradiation plus pembrolizumab followed by consolidation pembrolizumab in resectable stage IIIA non-small cell lung cancer.
Authors: Lemmon Christopher , Videtic Gregory M.M. , Murthy Sudish C. , Stephans Kevin L. , Shapiro Marc A. , Ahmad Usman , Raymond Daniel , Velcheti Vamsidhar , Bribriesco Alejandro , Pennell Nathan A.
Published: May 2020

9009

Background: Patients (pts) with resectable stage IIIA non-small cell lung cancer (NSCLC) have high rates of recurrence despite concurrent chemoradiation (CRT) followed by surgery. Immune checkpoint inhibitor consolidation has improved outcomes in unresectable stage III pts. Here we report the addition of concurrent neoadjuvant pembrolizumab (P) to CRT in stage IIIA patients to determine the safety and feasibility of this approach. Methods: Pts with stage IIIA NSCLC deemed resectable by a thoracic surgeon received neoadjuvant CRT consisting of cisplatin, etoposide, and concurrent P (200mg every 3 weeks x 3) with 45 Gy in 25 fractions. Pts without progression underwent resection followed by 6 months of consolidation P. The primary objective was feasibility and safety (defined as ≤30% grade 3 or higher pulmonary toxicity or any grade 4/5 nonhematologic toxicity). Ten pts were to be enrolled in Part 1, and if 2 or fewer pts had events then an additional 10 pts were to be enrolled. Secondary objectives were progression free survival (PFS), overall response rate (ORR), and pathologic complete response rate (pCR). Results: The median age of 9 enrolled pts was 66 years (range 49-76). 67% were female. 8 pts were assessable for radiographic response with an ORR of 75%. One pt came off study for progression prior to surgery and one had pleural metastases found during surgery so resection was aborted. Six pts underwent complete resection with a pCR rate of 67% (4/6). Consolidation P was started on 4 pts, with 3 completing treatment and 1 declined further treatment after 3 cycles. Median follow-up is 19.6 months and median PFS has not been reached. None of the patients who underwent resection have recurred. Serious adverse events were reported in all 9 pts with most significant being 2 grade 5 events: 1 due to pneumocystis pneumonia after resection but prior to consolidation, and 1 due to cardiac arrest during the neoadjuvant phase. Grade 3 events included 1 episode each of pneumonitis, bronchopleural fistula, acute kidney injury, colon perforation, and febrile neutropenia. Conclusions: The addition of P to neoadjuvant CRT in resectable stage IIIA pts resulted in a high pCR rate at resection. Although the relationship between grade 5 events and the addition of P was not clear, the stopping rule for infeasibility was met. As other larger studies are underway, the trial was halted rather than amended. This investigator initiated trial was funded by Merck. Clinical trial information: NCT02987998.
Consolidation nivolumab/ipilimumab versus nivolumab following concurrent chemoradiation in patients with unresectable stage III NSCLC: A planned interim safety analysis from the BTCRC LUN 16-081 trial.
Authors: Yan Melissa , Durm Greg Andrew , Mamdani Hirva , Ernani Vinicius , Jabbour Salma K. , Naidoo Jarushka , Hrinczenko Borys , Leal Ticiana , Feldman Lawrence Eric , Kloecker Goetz H. , Fujioka Naomi , Fidler Mary J. , Hanna Nasser H.
Published: May 2020

9010

Background: Consolidation PD-1/PD-L1 inhibition after chemoradiation (CRT) for unresectable stage III NSCLC improves overall survival. In stage IV NSCLC, the combination of nivolumab/ipilimumab improved overall survival compared to chemotherapy in patients with PD-L1 > 1% and performed favorably in patients with PD-L1 < 1%. The safety of consolidation nivolumab/ipilimumab after CRT has not been previously assessed. Methods: In this randomized, multi-center, phase II study, a total of 105 planned pts with unresectable stage IIIA/IIIB NSCLC will receive chemoradiation, then randomize 1:1 to either nivolumab 480mg IV q4 wks (Arm A) or nivolumab 3mg/kg IV q2 wks + ipilimumab 1mg/kg IV q6 wks (Arm B), for up to 24 wks. In this planned interim analysis, the safety of the first 50 patients, with 25 patients treated on each arm, is assessed. Results: From 9/2017 to 6/2019, the first 50 patients were accrued and analyzed for this planned safety analysis. Baseline characteristics for Arm A/B: median age 64/62, stage IIIA 17/16, stage IIIB 8/9, non-squamous 14/13, squamous 11/12. The median number of cycles completed in Arm A was 6 (range 1-6, cycle length q4 wks) and in Arm B was 4 (range 1-4, cycle length q6 wks). The rate of treatment-related adverse events leading to discontinuation of therapy was 16% in Arm A and 40% in Arm B. The percentage of patients with any > grade 3 adverse event (AE) was 32% in Arm A and 44% in Arm B. With respect to immune-related AE (irAEs), the percentage of patients with any ≥grade 2 was 44% in Arm A and 60% in Arm B; any ≥ grade 3 irAEs was 16% in Arm A and 32% in Arm B. The incidence of > grade 2 pneumonitis was 16% in Arm A and 36% in Arm B. The percentage of patients with > grade 3 pneumonitis was 4% in Arm A and 20% in Arm B. No treatment-related deaths were reported on either arm. Conclusions: In the post chemoradiation setting, the incidence of > grade 3 toxicity was greater in the consolidative nivolumab/ipilimumab arm, which resulted in a higher rate of treatment discontinuation than nivolumab alone. The Data and Safety Monitoring Board recommended continued enrollment without modification to the trial and the study currently remains open to accrual (66 of 105 patients have been enrolled as of 1/17/2020). Clinical trial information: NCT03285321.