bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carfilzomib-associated cardiovascular adverse events: A systematic review and meta-analysis.
Authors: Waxman Adam Justin , Chandra Clasen Suparna , Garfall Alfred L. , Carver Joseph R. , Vogl Dan T. , O'Quinn Rupal , Cohen Adam D. , Stadtmauer Edward Allen , Ky Bonnie , Weiss Brendan M. 
Published: September 2018

8018 Background: The incidence and nature of cardiovascular adverse events (CVAEs) with carfilzomib (CFZ) in multiple myeloma (MM) remain incompletely defined. We performed the first systematic review and meta-analysis of CFZ CVAEs. Methods: PubMed was queried for the keywords “carfilzomib,” “Kyprolis,” and “PX-171.” Phase 1-3 clinical trials of carfilzomib in MM with evaluable toxicity data were included. CVAEs were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grade ≥3 CVAEs and study characteristics were recorded. Summary incidence rates and relative risks (for randomized trials) with 95% confidence intervals were calculated using the logistic-normal random-effects model. Subgroup analyses were performed using study level covariates. Results: 514 studies were reviewed. 2623 MM patients from 25 eligible studies were included. Incidence rates are summarized in the table. All grade and grade ≥3 CVAEs were seen in 16.8% and 7.6 %, respectively. Phase 2 or 3 studies, carfilzomib doses ≥45mg/m2, and longer infusion length were study characteristics associated with high-grade cardiac AEs (p<0.05). Median age >65, prior MM therapies, and concurrent MM therapies were not associated with CVAEs (p>.05). For the three randomized trials, the relative risk of all-grade and grade ≥3 CVAEs were 1.75 and 2.25, respectively (p<0.001). Conclusions: CFZ is associated with a significant incidence of CVAEs, including heart failure, hypertension, ischemia, and arrhythmia. Phase I studies may be underdetecting CVAEs. Future studies are needed to: identify patients at high-risk for CVAEs, develop optimal monitoring strategies, and explore therapies to mitigate these risks. [Table: see text]
Prognostic impact of kinetics of circulating plasma cells before and after induction therapy in newly diagnosed multiple myeloma patients undergoing early transplantation.
Authors: Chakraborty Rajshekhar , Muchtar Eli , Dispenzieri Angela , Lacy Martha , Buadi Francis , Dingli David , Hogan William J. , Kumar Shaji , Jevremovic Dragan , Hayman Suzanne R. , Kapoor Prashant , Leung Nelson , Gertz Morie A. 
Published: September 2018

8020 Background: Circulating plasma cells (CPCs) at diagnosis, prior to transplant and at relapse have a negative prognostic impact on survival in multiple myeloma (MM). However, the impact of changes in CPCs along the course of illness has not been defined. Methods: We evaluated 247 patients with newly diagnosed MM (NDMM) undergoing early autologous stem cell transplantation (ASCT) in the era of novel agents (2007 to 2015), who had serial evaluation of CPCs at diagnosis and pre-ASCT by 6-color flow cytometry. Results: The median age at transplant was 62 years.A total of 117 (47%) patients had no detectable CPCs at both time points (CPC-/-), 82 (33%) had CPCs at diagnosis followed by complete eradication after induction therapy (CPC+/-) and 48 (19%) had detectable clonal CPCs at transplant, with persistence of cells (CPC+/+; n=45) or emergence of new CPCs (CPC-/+; n=3) after induction. The incidence of t(11;14) by iFISH was lower in the CPC-/- group (19%) compared to CPC+/- (29%) and CPC +/+ or -/+ (39%) groups ( p=0.033). Conversely, the incidence of hyperdiploidy was significantly higher in patients with CPC-/-, compared to those with CPC+/- and CPC+/+ or -/+ (64%, 44% and 39% respectively; p=0.005). The rate of post-ASCT stringent complete response was 32% in the CPC-/- group, 30% in CPC+/- group and 12% in CPC+/+ or -/+ group ( p=0.018). At a median follow-up of 58 months from ASCT, the median progression-free survival (PFS) from transplant in the 3 respective groups was 30, 24 and 14 months and the 5-year overall survival (OS) rates were 83%, 70% and 43% ( p<0.001 for both comparisons). On a multivariate analysis, using CPC-/- group as the comparator, PFS and OS was significantly inferior in CPC+/- (RR 1.6; p=0.020 and RR 2.7; p=0.008 for PFS and OS respectively) and CPC +/+ or -/+ groups (RR 2.9; p<0.001 and RR 5.8; p<0.001 for PFS and OS respectively). Conclusions: Clonal CPCs are detectable in more than 50% of newly diagnosed MM patients undergoing upfront ASCT. Monitoring for CPCs before initiation of induction therapy and before ASCT by 6-color flow cytometry is highly predictive of outcome in NDMM and should be incorporated into prospective clinical trials.
Daratumumab, lenalidomide, and dexamethasone (DRd) vs lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): Efficacy and safety update (POLLUX).
Authors: Bahlis Nizar J. , Moreau Philippe , Nahi Hareth , Plesner Torben , Goldschmidt Hartmut , Suzuki Kenshi , Orlowski Robert Z. , Rabin Neil , Leiba Merav , Oriol Albert , Chari Ajai , San Miguel Jesus , Richardson Paul G. , Usmani Saad Zafar , O'Rourke Lisa Marie , Wu Kaida , Casneuf Tineke , Chiu Christopher , Qin Xiang , Dimopoulos Meletios A. 
Published: September 2018

8025 Background: Daratumumab (D) is a human CD38-targeting mAb that significantly prolongs progression-free survival (PFS) when added to standard-of-care regimens in patients (pts) with RRMM. We examined updated efficacy and safety data from POLLUX (NCT02076009), a randomized phase 3 study of DRd vs Rd in RRMM. Methods: Pts with ≥1 prior line of therapy (LOT) received Rd (25 mg PO lenalidomide on days 1-21 of each q4w cycle; 40 mg dexamethasone weekly) ± D (16 mg/kg IV qw for cycles 1 and 2, q2w for cycles 3-6, then q4w until disease progression). Pts refractory to lenalidomide were ineligible. Minimal residual disease (MRD) was assessed on bone marrow samples at time of suspected complete response (CR) and at 3 and 6 months post-suspected CR at sensitivities of 10–4, 10–5, and 10–6 via next-generation sequencing (Adaptive Biotechnologies, Seattle, WA). Results: Pts received a median (range) of 1 (1-11) prior LOT. 55% received prior IMiDs (18% lenalidomide). Based on previous median follow-up of 17.3 months, DRd significantly prolonged PFS (median: not reached vs 17.5 months; HR, 0.37; 95% CI, 0.28-0.50; P< 0.0001) and significantly improved overall response rate (ORR; 93% vs 76%, P< 0.0001) vs Rd. DRd induced higher rates of deep responses vs Rd (≥very good partial response [VGPR]: 78% vs 45%; ≥CR: 46% vs 20%; all P< 0.0001) and included MRD negativity, which was > 3-fold higher across all 3 sensitivity thresholds for DRd vs Rd (25% vs 6% at the 10–5 threshold). MRD-negative pts demonstrated longer PFS vs MRD-positive pts. Follow up for overall survival (OS) is ongoing (OS events: 40 [14%] in DRd and 56 [20%] in Rd). No new safety signals were identified with longer follow up. Updated efficacy and safety data based on approximately 25-months follow up will be presented at the meeting. Conclusions: DRd provided significant benefits vs Rd in terms of PFS, ORR, and MRD negativity, and the favorable safety profile of DRd was maintained with longer follow up. These data further validate the use of DRd in RRMM pts who received ≥1 prior therapy. Clinical trial information: NCT02076009.
Impact of metformin use in the outcomes of multiple myeloma patients post stem cell transplant.
Authors: Duma Narjust , Vera Aguilera Jesus , Paludo Jonas , Wang Yucai , Anagnostou Theodora , Fonder Amie L. , Buadi Francis , Kumar Shaji , Lacy Martha , Hayman Suzanne R. , Dispenzieri Angela , Gertz Morie A. , Dingli David 
Published: September 2018

8034 Background: Multiple myeloma (MM), a monoclonal plasma cell disorder, is one of the most common hematologic malignancies in the US. In preclinical studies, metformin demonstrated plasma cells cytotoxicity. However, there is lack of studies translating the effect of metformin into the clinical setting. Therefore, we assessed the clinical effect of metformin in patients (pts) with MM. Methods: All MM pts who underwent stem cell transplant (SCT) at the Mayo Clinic Rochester from 2007 to 2012 were reviewed. Patients were grouped based on metformin use. Initial diagnosis at our institution and ≥12 months of follow up were required. Kaplan-Meier method and Cox regression were used for time-to-event and multivariate analysis. Results: Out of 687 pts, 78 (11.4%) were using metformin at the time of MM diagnosis. Baseline characteristics in the metformin (Mt) and no-metformin (NMt) groups were similar (Table). Median (M) metformin dose was 2000 mg daily and m duration of metformin use from MM diagnosis was 22 months. Pts on the Mt group achieved higher rates of CR after SCT (41% vs. 29%, p<0.02). Median PFS after SCT was longer in the Mt group, 31.3 months (95% CI: 10.4-52.2) vs. 16.6 months in the NMt group (95%CI: 14.5-18.7) p<0.04. There was a trend towards longer OS in the Mt group, but it was not statistically significant (170 vs. 106 months, p<0.10). In a multivariate analysis of metformin use, age, ISS, LDH, and cytogenetics/FISH, the former was an independent predictor of PFS after SCT (OR: 0.38, 95%CI: 0.20-0.68, p<0.001). Conclusions: Metformin use was associated with a better PFS and higher CR after SCT in our MM cohort. A trend towards better OS was also noted in the Mt group. Larger studies are needed to enhance our understanding of the clinic effect of metformin on MM. [Table: see text]
Impact of post-autologous stem cell transplant (ASCT) maintenance therapy on outcomes in patients (Pts) with newly diagnosed multiple myeloma (NDMM) using the large prospective community-based Connect MM registry.
Authors: Jagannath Sundar , Abonour Rafat , Durie Brian G. , Shah Jatin J. , Narang Mohit , Terebelo Howard R. , Gasparetto Cristina , Toomey Kathleen , Hardin James W. , Wagner Lynne I. , Agarwal Amit , Srinivasan Shankar , Kitali Amani , Zafar Faiza , Sturniolo Michael , Rifkin Robert M. 
Published: September 2018

8040 Background: Maintenance therapy (MT) improved progression-free survival (PFS) and overall survival (OS) in MM clinical trials. The observational Connect MM registry, which is largely community based, was used to assess impact of MT on outcomes in ASCT-eligible NDMM pts. Methods: Adult NDMM pts ≤60 days from diagnosis were eligible for enrollment. Pts receiving induction and ASCT were included and analyzed by 4 MT regimens: No MT, lenalidomide-based (LEN), bortezomib-based (BORT), and LEN+BORT MT. Duration was from 100 days post-ASCT (no MT group) or start of MT until progressive disease, death, discontinuation, or data cutoff. End points were PFS, 2nd PFS, OS, and safety. An exploratory analysis of the impact of baseline characteristics was performed. Results: Of 1493 enrolled pts (Cohort 1; Sep 2009 – Dec 2011), 1450 were treated; 81% (n=1173) were in a community setting. A total of 432 (29%) met analysis criteria. Data cutoff was Jan 7, 2016 (median follow-up of 39.3 mo). Median age was 60 y (range, 24-78 y); 60%, men; and 86%, white. 165 pts did not receive MT. Of 267 pts receiving MT, 213 (80%) received LEN; 30 (11%), BORT; and 16 (6%), LEN+BORT. Only LEN MT is presented, as interpretation of other MT data was limited by small sample sizes. Median treatment duration for LEN MT vs No MT was 35.2 vs 26.1 mo, respectively. PFS and OS significantly increased with LEN MT vs No MT (Table); 2nd PFS was similar for both. Exploratory analyses showed generally similar PFS and OS improvements across subgroups (age, ECOG status, ISS stage, risk group, and induction regimen). No new safety signals were observed. Conclusions: In ASCT-eligible NDMM pts, PFS and OS improved with LEN MT vs No MT and appeared to be independent of induction regimen. Preliminary analysis of 2nd PFS suggests no impact on the efficacy of 2nd line therapy. These data from a largely community-based setting confirm results from randomized phase III trials. Clinical trial information: NCT01081028. [Table: see text]
Outcomes of secondary cancers among myeloma survivors.
Authors: Castillo Jorge J. , Olszewski Adam J. 
Published: September 2018

8043 Background: With increasing survival, myeloma patients (pts) experience second cancers. We analyzed receipt of surgery and cancer-specific survival (CSS) among myeloma survivors with common solid tumors, in comparison with pts without myeloma. Methods: We extracted Surveillance, Epidemiology, and End Results (SEER) data on pts diagnosed with common cancers in 2004-2013. Among them, we identified myeloma survivors, and we matched each to 50 randomly sampled controls with the same cancer by age, sex, race, and year of diagnosis. We then compared CSS, cumulative incidence function (CIF) for death from the index cancer (but not from myeloma), and receipt of surgery (for non-metastastic, stage-matched tumors only) using a Cox (for hazard ratio, HR), Fine-Gray (for subhazard ratio, SHR), and conditional logistic models, respectively. Results: Myeloma survivors were significantly older ( P<.001), and more often black (except in bladder cancer) than pts with respective cancers from the general population. In the case-control analysis, breast ( P=.002) and lung cancers ( P=.003) were more often diagnosed at an early stage among myeloma survivors. Receipt of surgery did not significantly differ, except for lower use of prostatectomy in myeloma survivors (odds ratio, 0.59, 95%CI, 0.44-0.81). CSS significantly differed only in lung cancer, and was better among myeloma survivors even when stratified by stage. CIF of cancer death was significantly lower for myeloma cases with lung and colorectal cancer. Conclusions: Despite additional competing mortality from recurrent myeloma, myeloma survivors have similar CSS and CIF of death after common cancers compared with other pts. This highlights the need to treat them similarly to other pts, without assuming a poor prognosis. Better outcomes in lung cancer are not fully explained by earlier detection, suggesting a biological difference. [Table: see text]
AFM26 is a novel, highly potent BCMA/CD16A-directed bispecific antibody for high affinity NK-cell engagement in multiple myeloma.
Authors: Gantke Thorsten , Reusch Uwe , Kellner Christian , Ellwanger Kristina , Fucek Ivica , Weichel Michael , Kerber Anne , Peipp Matthias , Treder Martin 
Published: September 2018

8045 Background: Despite recent advances in the treatment of multiple myeloma (MM), novel therapies are needed to achieve long-lasting remissions in a greater number of patients. Natural killer (NK) cells play a key role in the immune response to MM and have been implicated in the clinical efficacy of current standard of care interventions, including IMiDs, proteasome inhibitors, recently approved immunotherapies and autologous stem cell transplantation (ASCT). Numerous strategies are being developed to enhance the natural NK-cell cytotoxicity against myeloma cells, which is frequently dysregulated in MM. Approaches include modulation of activity, through cytokine stimulation or immune checkpoint targeting, and adoptive transfer of culture expanded NK-cells in ASCT-eligible MM. While highly attractive, these approaches are non-targeted, as they rely on the natural cytotoxicity of NK-cells, and may benefit from antigen-specific retargeting and effector activation. AFM26 is a novel tetravalent, bispecific antibody designed to specifically enhance NK-cell anti-MM activity by redirecting NK-cell lysis to BCMA, an antigen expressed on MM cells. Methods: NK-cell engagement and cytotoxicity of AFM26 towards MM cell lines and freshly isolated tumor cells from MM patients was characterized in vitro and compared with classical antibody formats. Results: AFM26 engages NK-cells with superior avidity ( KD: 1-2nM) through bivalent interaction with CD16A (FcγRIIIa) and demonstrates extended cell surface retention that is not affected by high level IgG, as is particularly relevant in MM. Importantly, AFM26 does not induce NK-cell depletion but selectively induces potent and efficacious lysis of MM cells in vitro. Conclusions: In summary, AFM26 is a promising candidate to enhance NK-cell activity and confer tumor-specificity to NK-cells in MM. Differentiation of AFM26 from classical antibody formats and its potential for combination with cellular NK-cell therapies is highlighted.
Risk stratification by detection of clonal circulating plasma cells (CPCs) by multi-parametric flow cytometry (MFC) in light chain amyloidosis (AL).
Authors: Sidana Surbhi , Tandon Nidhi , Dispenzieri Angela , Gertz Morie A. , Buadi Francis , Lacy Martha , Dingli David , Fonder Amie L. , Hayman Suzanne R. , Hobbs Miriam A. , Hwa Yi Lisa , Kapoor Prashant , Kyle Robert A. , Leung Nelson , Go Ronald S. , Lust John Anthony , Russell Stephen J. , Rajkumar S. Vincent , Kumar Shaji , Gonsalves Wilson I. 
Published: September 2018

8047 Background: Presence of CPCs by six color MFC is associated with worse outcomes in multiple myeloma (MM). Using a slide based immunofluorescence assay, CPCs are associated with worse prognosis in AL, but outcomes with MFC are not known. Methods: We retrospectively analyzed 154 patients (pts) from Jan 2008 – Dec 2015 with AL who had CPCs analyzed by MFC at diagnosis. Results: CPCs were present in 42% pts (n = 64, median = 88 per 150,000 events, range 6-17844). Table 1 lists baseline characteristics, treatment and response. In univariate analysis, bone marrow (BM) plasma cells > 15% (p<0.0001), dFLC > 60 mg/dL (p=0.02) and presence of active MM (p=0.0004) were associated with detectable CPCs. In multivariate (MV) model, only BM plasma cells > 15% predicted for presence of CPCs (p=0.02). There was no difference in hematologic or organ response in the 2 groups. Median follow up was 43 months (m). Pts with detectable CPCs had worse survival than those without detectable CPCs (90 m vs. 98 m, p=0.0004). In MV analysis model with Mayo Stage and detectable CPCs, presence of CPCs at diagnosis was independently associated with poor survival (CPCs p= 0.02, Mayo Stage p < 0.0001). Conclusions: Presence of detectable CPCs is an independent adverse prognostic factor for survival in AL. Comparatively fewer pts with detectable CPCs underwent early ASCT, which may reflect a more aggressive disease presentation. [Table: see text]
Outcomes according to involved free light chain (FLC) levels in patients with normal FLC ratio after initial therapy in light chain amyloidosis (AL).
Authors: Tandon Nidhi , Sidana Surbhi , Dispenzieri Angela , Gertz Morie A. , Lacy Martha , Dingli David , Buadi Francis , Fonder Amie L. , Hayman Suzanne R. , Hwa Yi Lisa , Hobbs Miriam A. , Kapoor Prashant , Gonsalves Wilson I. , Leung Nelson , Go Ronald S. , Lust John Anthony , Russell Stephen J. , Kyle Robert A. , Rajkumar S.Vincent , Kumar Shaji 
Published: September 2018

8049 Background: Complete response in AL is defined as normal FLC ratio with negative serum and urine immunofixation. It is not clear if high involved serum FLC (hIFLC) in a patient with normal ratio may contribute to ongoing amyloid formation and hence affect outcomes. Methods: Data of 1308 patients (pts) with systemic AL seen within 90 days of diagnosis, at Mayo Clinic between 2006-2015, was analyzed retrospectively. Among these, 369 pts had 2 consecutive normal FLC ratio values after 1st line treatment and form the study population. Log rank test was used to estimate survival differences. Results: Among these 369 pts, pts with hIFLC at 1streading of normal FLC ratio (hIFLC1; n=170; 46.1%) were compared to those who did not (n=199; 53.9%). At diagnosis, the median age [61.5 vs 60.8 years (y); p=0.2], proportion of males (62.4 vs 58.3%; p=0.4), percentage of pts with renal involvement (73.5 vs 64.8%; p=0.07), in mayo stage I / II / III / IV (32.9% / 23%/ 27.3% / 16.8% vs 43.6 %/ 22.9% / 18.1% / 15.4%; p=0.1), with bone marrow plasma cells >10% (24.2 vs 30%; p=0.2) and with presence of t(11; 14)(48.4 vs 60; p=0.08) was similar, while cardiac (67.5 vs 53.3%; p=0.006) and hepatic (18.2 vs 9.1%; p=0.01) involvement was higher in hIFLC1 group. The median follow-up from diagnosis was 6.1 y (95% CI; 5.6, 6.8). The median progression free survival (PFS) in pts who had hIFLC1 was lower than for those who did not; 2.6 y (95% CI; 1.9, 4.5) vs 5.2 y (95% CI; 4.6, 6.4), p<0.0001, as was the median overall survival [OS; 6.7 y (95% CI; 4.5, 8.3) vs not reached (NR), p<0.0001]. We performed a more stringent comparison for pts with 2 consecutive hIFLC values (hIFLC2; n=112; 30.4%) versus not (n=257; 69.6%). The median PFS (3.2 y; 95%CI; 2.2, 4.5 vs 5.6 y; 95% CI; 4.7, 7.1; p<0.0001) and OS (7.8 y; 95% CI; 6.4, NR vs NR; 95%CI; 9.5, NR; p<0.0001) were significantly reduced in pts with hIFLC2 versus not as well. A multivariate analysis confirmed an impact of hIFLC1 and hIFLC2 on PFS/OS independent of serum creatinine. Conclusions: In pts with systemic AL, persistent elevation of the involved FLC predicts for poor prognosis (independent of serum creatinine) even among those who achieved normal FLC ratio after 1st line treatment.
Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers: Results from a phase II basket trial.
Authors: Li Bob T. , Shen Ronglai , Buonocore Darren , Olah Zachary T. , Ni Ai , Ginsberg Michelle S. , Ulaner Gary , Weber Wolfgang , Ladanyi Marc , Won Helen H. , Riely Gregory J. , Solit David B. , Hyman David Michael , Rudin Charles M. , Berger Michael F. , Scaltriti Maurizio , Baselga Jose , Kris Mark G. , Arcila Maria E. 
Published: September 2018

8510 Background: Human epidermal growth factor receptor 2 ( HER2, ERBB2) mutations occur in 2% of lung cancers, resulting in receptor dimerization and kinase activation with in vitro sensitivity to trastuzumab. Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate linking trastuzumab with the anti-microtubule agent emtansine. Methods: Patients (pts) with HER2 mutant lung cancers were enrolled into a cohort of the basket trial of ado-trastuzumab emtansine in HER2amplified or mutant cancers, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1. A Simon two stage optimal design was used with type I error rate under 2.7% (and a family wise error rate across baskets under 10%), power of 89%, H0 10%, H1 40%; the H0 will be rejected if 5 or more responses are observed in 18 pts. Other endpoints include duration of response (DOR), progression-free survival (PFS) and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing (NGS), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Results: The cohort completed accrual with 18 pts treated. The median age was 63 (range 47-74 years), 72% were female, 39% were never smokers and all had adenocarcinomas. The median lines of prior systemic therapy was 2 (range 0-4). ORR was 33% (5/15 confirmed, 95% CI 12-62%) not including a partial response awaiting confirmation and 3 pts pending response evaluation. Median DOR was not reached (range 3 to 7+ mo), median PFS was 4mo (95% CI 3mo-not reached). Toxicities were mainly grade 1 or 2 including infusion reaction, thrombocytopenia and transaminitis, there were no dose reductions or treatment related deaths. There were 10 (56%) exon 20 insertions and 8 (44%) point mutations; responders were seen across mutation subtypes (A775_G776insYVMA, G776delinsVC, V659E, S310F). HER2amplification was negative for all pts by NGS and positive for 1 of 12 pts by FISH. There was no IHC3+ in 10 pts tested. Conclusions: Ado-trastuzumab emtansine is active and well tolerated in pts with HER2 mutant lung cancers. This study has met its primary endpoint. Further development in a multicenter study is warranted. Clinical trial information: NCT02675829.