bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of once-weekly carfilzomib (K) dosing in frail patients (pts): A subgroup analysis from the phase 3 A.R.R.O.W. study.
Authors: Mateos Maria-Victoria , Ludwig Heinz , Kumar Shaji , Rosenbaum Cara Ann , Huang Mei , Goldrick Amanda , Blaedel Julie , Dimopoulos Meletios A. 
Published: March 2020

8027 Background: A.R.R.O.W. demonstrated superior progression-free survival (PFS) with once-weekly K (70 mg/m2)-dexamethasone (Kd70) vs twice-weekly K (27 mg/m2)-dexamethasone (Kd27) in relapsed and refractory multiple myeloma (RRMM) pts, regardless of age. Weekly Kd70 is US-approved for relapsed or refractory MM (1–3 prior therapy lines). For a comprehensive fitness measure, frailty scales were developed incorporating age, comorbidities, and functional status. (Palumbo Blood 2015; Facon Blood 2015). Here we assessed post hoc pt outcomes by frailty status. Methods: PFS and safety were assessed by treatment arm and a frailty algorithm incorporating age, medical history–derived Charlson Comorbidity Index, and ECOG performance status; pts with frailty scores of 0, 1, or ≥2 were classified as fit, intermediate (int), or frail, respectively. PFS was assessed with the Kaplan-Meier method. Safety was assessed in pts who received ≥1 treatment dose. Results: Pt distribution by frailty status was generally balanced between arms (Table). Once-weekly Kd70 vs twice-weekly Kd27 resulted in median PFS for fit, int, and frail pts of 15.7 vs 5.7 (mos; HR 0.53 [95% CI, 0.33–0.86]), 11.1 vs 7.7 mos (HR 0.81 [95% CI, 0.55–1.19]), and 10.3 vs 6.6 mos (HR 0.76 [95% CI, 0.49–1.16]), respectively. Rates of grade ≥3 treatment-emergent adverse events (TEAEs) of interest were similar between treatment arms across frailty subgroups (Table). In the once-weekly Kd70 subgroups, there was no grade ≥3 peripheral neuropathy (PN); grade ≥3 cardiac failure rates were ≤4%. Conclusions: Once-weekly Kd70 resulted in PFS benefits vs twice-weekly Kd27 with a favorable benefit/risk profile regardless of frailty score as defined. These results support weekly Kd70 as a treatment option for both fit and frail RRMM pts. Clinical trial information: NCT02412878. [Table: see text]
Implications and outcomes of MRD-negative multiple myeloma patients with immunofixation positivity.
Authors: Tschautscher Marcella , Jevremovic Dragan , Buadi Francis , Lacy Martha , Gertz Morie A. , Dispenzieri Angela , Kapoor Prashant , Dingli David , Hayman Suzanne R. , Lust John Anthony , Russell Stephen J. , Leung Nelson , Go Ronald S. , Lin Yi , Gonsalves Wilson I. , Kourelis Taxiarchis , Warsame Rahma M. , Kyle Robert A. , Rajkumar S. Vincent , Kumar Shaji 
Published: March 2020

8034 Background: Minimal residual disease (MRD) assessment in multiple myeloma (MM) has improved our ability to assess disease activity, resulting in more advanced prognostication. While MRD assessment remains confined to the bone marrow (BM) plasma cell population, serum studies including immunofixation (IFE) are required to complete response evaluation. The significance of those who are MRDneg yet have detectable monoclonal protein through IFE remains unclear. Methods: We retrospectively studied 256 MM patients who had MRD assessment via the Euroflow multiparametric flow cytometry on the BM with concomitant serum IFE testing. Patients who were MRDneg were included in the study. Outcomes included probability of disease progression (PD) at 1 year. The Cox-proportional hazards model was used to compare probability of PD among different groups. Time to progression (TTP) was calculated as the difference from date of MFC analysis to PD in months. Results: Among the entire cohort, 178 (70%) patients were MRDneg and median follow-up from MRD assessment was 6.3 months. Among these patients, 74 (42%) had a positive IFE at the time of MRD analysis. Within the MRDneg/IFEpos group, 31 (42%) patients remained IFEpos after a median follow up of 5.5 mo from initial MRD/IFE testing while 34 patients eventually became IFEneg after a median of 2.8 mo with no subsequent IFE available in 9 patients. The 1 year probability of PD in the MRDneg/IFEneg group was 20% compared to 41% in the MRDneg/IFEpos group (P < 0.01, Wilcoxon test). When comparing subsequent IFE status in those who were MRDneg/IFEpos, those who remained IFEpos had a trend towards shorter TTP compared to patients who later became IFEneg. Conclusions: Persistent monoclonal protein in the face of MRD negativity predicts for a shorter TTP. This likely reflects persistent disease that was not sampled on the BM aspirate in many of these patients compared to those who eventually become IFEneg with a trend towards longer TTP owing to the prolonged half-life and therefore clearance of M protein. This supports the current strategy of assessing for MRD at the time of suspected complete response to reduce the chance of positive MRD tests and thus avoidance of multiple BM exams.
Plasma cell-free DNA chromosomal instability score as early predictor to monitor tumor burden in response to therapeutic in multiple myeloma patients.
Authors: Du Juan , Jia Yanchun , Qiang Wanting , Lu Jing , Li Lu , Jiang Hua , Ziliang Qian , Fu Weijun 
Published: March 2020

8036 Background: Multiple myeloma (MM) is a plasma cell malignancy characterized by chromosomal instabilities (CIN). Here we investigate the potential of cell-free DNA CIN as non-invasive biomarker to predict early response for MM treatments. Methods: In this prospective study, we recruited 11 relapsed/refractory (RRMM) and 19 newly diagnosed (NDMM) patients at Changzheng Hospital. Plasma samples were collected after finished two cycles or one month (RRMM) of therapy, with matched ones before the current regimen. cfDNA was extracted, followed by CIN analyses by using a customized bioinformatics workflow, ultrasensitive chromosomal aneuploidy detector (UCAD). Criteria for response and progression were according to the IMWG (Durie BG et al. 2006). Results: 7 (23%) patients (5 RRMM and 2 NDMM) showed high cfDNA CIN regard as strong positive after two cycles of treatment. Plasma cfDNA CIN profiling found complex clonal evolution compared two cycles to baseline. Multiple genomic regions, including chr7, 17p (TP53), 12q and 3p, were involved in clonal evolution. The degree of cfDNA CIN correlated with myeloma stage and overall survival. Remarkably, of the 5 heavily treated RRMM patients and 1 primary refractory newly diagnosed patient, 3 died within 60 days after the last time of cfDNA detection. Nine patients (30%) of patients showed positive cfDNA CIN after two cycles of treatment, which response rate was 11% (n=1) with SD, 33% (n=3) with MR, and 56% with PR, respectively. Fourteen patients with 5 RRMM and 9 NDMM were detected marginal or negative cfDNA CIN after two cycle’s treatment. The overall response rate in 14 patients was 100%, including 14.3% with a complete response, 14.3% with a very good partial response (VGPR), 57.1% with a PR, and 14.3% with a MR. Of these patients, 3 RRMM who received with more than six lines of therapy, showed positive cfDNA CIN. Subsequently, these three heavily treated RRMM patients have chance to enroll the chimeric antigen receptor T-Cell immunotherapy (CAR-T) therapy (enrolled NCT03093168). Surprisedly, all of them benefit from the CAR-T therapy to improve responses dramatically, meanwhile, the dynamics of total cfDNA concentration correlated with tumor burden to negative. Conclusions: We provide evidence that cfDNA level correlates with tumor burden and response rate in MM. For heavily pre-treated advanced RRMM patients with cfDNA CIN positive were benefit from the CAR-T therapy. Therefore, serial plasma cfDNA analysis is a robust and sensitive tool for monitoring response to therapy.
Efficacy and safety of daratumumab, lenalidomide, and dexamethasone (D-Rd) in relapsed or refractory multiple myeloma (RRMM): Updated subgroup analysis of POLLUX based on cytogenetic risk.
Authors: Kaufman Jonathan L. , Dimopoulos Meletios A. , Leiba Merav , Morton James , Ho P. Joy , Kim Kihyun , Moreau Philippe , Sutherland Heather J , Iida Shinsuke , Kim Jin Seok , Prince H. Miles , Rocafiguera Albert Oriol , Bahlis Nizar J. , Chari Ajai , Avet-Loiseau Herve , Chiu Christopher , Soong David , Ukropec Jon , Qi Ming , San Miguel Jesus 
Published: March 2020

8038 Background: High-risk cytogenetic abnormalities confer poor outcomes in MM patients (pts). In POLLUX, D-Rd demonstrated significant clinical benefit, including prolonged progression-free survival (PFS) vs lenalidomide and dexamethasone (Rd), and tolerability in RRMM pts. We present a subgroup analysis of POLLUX, based on cytogenetic risk. Methods: Pts had ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of fluorescence in situ hybridization/karyotype testing and next-generation sequencing (NGS). High-risk pts had t(4;14), t(14;16), or del17p abnormalities; standard (std)-risk pts did not meet high-risk criteria. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ® assay V2.0. Results: In POLLUX (D-Rd, n = 286; Rd, n = 283), 17.1% of pts in the D-Rd group and 20.1% of pts in the Rd group had high-risk abnormalities. After 44.3 months (mo) of median follow up, D-Rd prolonged PFS vs Rd in pts with high- (median 26.8 vs 8.8 mo; HR, 0.54 [95% CI, 0.32-0.91]; P = 0.0175) or std-risk (median not reached [NR] vs 19.9 mo; HR, 0.41 [95% CI, 0.31-0.55]; P <0.0001). Responses with D-Rd were deep, including higher rates of MRD negativity and sustained MRD negativity vs Rd (Table). D-Rd prolonged PFS in first relapse pts (high risk: median 46.0 vs 7.3 mo; HR, 0.26 [95% CI, 0.11-0.59]; P = 0.0005; std risk: median NR vs 20.6 mo; HR, 0.43 [95% CI, 0.28-0.66]; P <0.0001) and prolonged PFS2 vs Rd in high- (median 38.3 vs 22.1 mo; HR, 0.53 [95% CI, 0.30-0.93]; P = 0.0249) or std-risk (median NR vs 33.8 mo; HR, 0.53 [95% CI, 0.39-0.72]; P <0.0001) pts. Additional data will be presented. Conclusions: D-Rd demonstrates significant efficacy in high-risk RRMM. Among high-risk pts, MRD negativity was only achieved with D-Rd. Clinical trial information: NCT02076009. [Table: see text]
Weekly 20/56 mg/m² carfilzomib, lenalidomide, and dexamethasone until progression in early relapsed refractory multiple myeloma.
Authors: Gruchet Cecile , Richez Valentine , Guidez Stephanie , Fouquet Guillemette , Azais Isabelle , Durand Geraldine , Javaugue Vincent , Plasse Florent , Machet Antoine , Moya Niels , Gardeney Helene , Bobin Arthur , Levy Anthony , Sabirou Florence , Bonnin Anthony , Dieval Celine , Primault Sylvain , Bridoux Frank , Avet-Loiseau Herve , Leleu Xavier 
Published: March 2020

8041 Background: Triplet-based Carfilzomib (K), Lenalidomide and Dexamethasone combination (KRd) has led to approval in early RRMM based on ASPIRE International phase 3 study. However, K was used on a twice a week basis at 27mg/m2 and limited to 18 months exposure. We have reported already that KRd on a weekly basis at 56 mg/m2 was active similar to ASPIRE KRd and safe. We report herein the long-term exposure data on KRd weekly given until progression. We aimed to evaluate the efficacy of KRd given on a prolong duration beyond 18months, and to validate the safety profile of continuous exposure to K. Methods: 28 patients were prospectively recruited. Carfilzomib 20/56mg/m2 was administered on days 1,8,15, Lenalidomide 25mg/day was given 21/28 days and Dexamethasone was administered weekly on 28 days cycles until progression. Results: With a median follow-up at start of KRd of 30 months, 50% of patients relapsed and 39% died. 24/28 patients received 1 prior line of treatment. 8/28 patients are still on treatment with duration > 24 month and 6/28 with duration > 30 months. The median number of cycles was 15. ORR and CBR was 85.7% and 89.3%, whom 46% ≥ CR ; with a median DOR of 13 months and 43% having more than 18 months. 6 patients had negative MRD at 10-6 and normalized PET CT. Median of OS is not reached, and the 30 month-expected OS from the start of KRd was 56%. The median PFS and EFS was at 29 months, and the 30 month-expected PFS and EFS was 45%. PFS and EFS being superimposable speaks to that there was no safety concern related to prolonged exposure to K. Only 4 patients stopped KRd for safety issues. Hematologic and non-hematologic adverse events ≥ grade 3 were reported in 16/28 and 10/28 patients. Adverse events ≥ grade 3 seen in ≥10% of patients were neutropenia, thrombocytopenia, vomiting and pyrexia. Of note, 5 patients (18%) were ≥ 65 years old and showed similar data compared to the cohort. Conclusions: KRd weekly is effective and safe to early in RRMM patients, provides improved safety profile to patients allowing treating patients until progression. Further studies are warranted to confirm this data on a larger early RRMM population and validate the concept of long duration of treatment using Carfilzomib combination.
A phase I trial of ruxolitinib, lenalidomide, and methylprednisolone for patients with relapsed/refractory multiple myeloma (MM).
Authors: Berenson James R. , To Jennifer , Spektor Tanya M. , Martinez Daisy , Sanchez Armando Jose , Ghermezi Matthew , Turner Carley , Swift Regina A. , Eades Benjamin M , Schwartz Gary , Eshaghian Shahrooz , Stampleman Laura , Moss Robert A. , Nassir Youram , Patel Ravindranath , Bessudo Alberto , Lim Stephen , Vescio Robert A. 
Published: March 2020

8048 Background: Preclinical studies from our laboratory have demonstrated that ruxolitinib (RUX) in combination with lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 is responsible for LEN resistance in MM cells, and RUX blocks its expression in MM cells. Thus, RUX may restore sensitivity to LEN. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and methylprednisolone (MP) for relapsed/refractory (RR) MM patients (pts) who had previously been treated with LEN/steroids and a proteasome inhibitor (PI) and showed progressive disease at study entry. Methods: A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment to be 49 pts. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, pts received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results: As of September 1, 2018, 36 pts were enrolled, and 32 were evaluable for efficacy. The median age was 66 years (range, 46-81), and 21 (58%) were male. Pts received a median of 6 prior treatments including LEN and steroids to which they were all refractory and a proteasome inhibitor. No DLTs occurred, and DL+3 was expanded. Among evaluable pts, the CBR and ORR were 47% and 41%, respectively (1 CR, 2 VGPR, 10 PR and 2 MR), and 14 and 3 pts showed SD and PD. All 15 responding pts were refractory to LEN. G3 AEs included anemia (17%), neutropenia (14%), sepsis (14%), lymphocytopenia (11%), thrombocytopenia (11%), and pneumonia (11%). Most common SAEs included sepsis (14%) and pneumonia (11%). Conclusions: This Ph 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RR MM pts. These promising results are leading to expansion of the current clinical trial to 78 pts, and represents a novel therapeutic approach for treating MM. Clinical trial information: NCT03110822.
Prognosis of young patients with monoclonal gammopathy of undetermined significance.
Authors: Pang Li , Kumar Shaji , Lakshman Arjun , Kyle Robert A. , Rajkumar S. Vincent 
Published: March 2020

8049 Background: Monoclonal gammopathy of undetermined significance (MGUS) is rare in young patients (pts; age <40 years at diagnosis), with a prevalence of < 0.3%, representing approximately 2% of all patients with MGUS. We hypothesized that MGUS detected in pts <40 years of age may be associated with a higher risk of progression. Methods: We identified 249 pts with MGUS <40 yrs old, evaluated at Mayo Clinic, Rochester from 1997 to 2016. The endpoint was time to progression assessed by Kaplan-Meier method. Results: 119 were male, 130 were female. Most (n= 179, 72%) were diagnosed between the ages of 30-39. The type of MGUS was IgG 69%, IgA 10%, IgM 15%, and other 5%. 135 pts (54%) had concurrent immune-related conditions, including autoimmune, inflammatory, and infectious disorders at the time of diagnosis of MGUS. Pts without immune-related conditions tend to have higher M protein compared to pts with immune-related conditions (mean, 0.36 gm/dl VS 0.20 gm/dl, p =0.057). During follow up, the M protein resolved in 36 patients. The M protein was more likely to resolve in pts with immune-related conditions compared with pts without immune-related conditions (RR 1.91, 95% CI 1.02-3.59). Progression was seen in 16 pts: 9 smoldering multiple myeloma (SMM), 4 multiple myeloma (MM), 1 macroglobulinemia, 2 non-Hodgkin’s lymphoma. The rate of progression to SMM, MM, or related disorder at 5 and 10 years was 6.0% and 13.8%, respectively. The size of M protein was a significant risk factor for progression (HR 4.23, 95% CI 2.17-7.91) The risk of progression at 5 and 10 years for pts with immune-related conditions concurrently present when MGUS was first diagnosed was 1.5% and 10.1% respectively; corresponding rate in pts without immune-related conditions at the time of diagnosis was higher at 12.3% and 18.9%, respectively (p =0.016), (HR 2.36, 95% CI 0.85-6.52). Similar results were seen when patients in whom the M protein resolved were excluded. Conclusions: Young patients with MGUS may have a higher risk of progression, 1.4% per year; approximately 50% are diagnosed in the setting of immune-related disorders. When occurring in the setting of immune related disorders, the M protein is smaller, more likely to resolve, and may have a lower risk of progression than in pts in whom MGUS is detected without concurrent immune-related disorder.
Phase I trial of a novel DNA vaccine in patients (pts) with smoldering Waldenstrom macroglobulinemia (sWM).
Authors: Thomas Sheeba K. , Cha Soungchul , Parshottam Sapna R , Rao Sheetal S , Olsem Jasper B. , Crumpton Brandon N. , Feng Lei , Lee Hans Chulhee , Manasanch Elisabet Esteve , Weber Donna M. , Patel Krina K. , Orlowski Robert Z. , Neelapu Sattva Swarup , Kwak Larry W. 
Published: March 2020

8050 Background: Idiotypic determinants of the surface immunoglobulin (Ig) associated with a given pt’s B-cell lymphoma are unique to that tumor, and thus are a tumor-specific marker. This study aims to use an idiotype DNA vaccine to lengthen the smoldering phase of WM without inducing cross-resistance to available therapies. Administered vaccine used recombinant plasmid DNA encoding a fusion protein, consisting of autologous lymphoma scFv (pt-specific idiotype) and human CCL20 (macrophage inflammatory protein-3 alpha - MIP-3α) chemokine. Targeted delivery of this fusion protein to APCs, and subsequent processing and presentation, is hypothesized to break tolerance and generate an immune response against the idiotype, promoting eradication of antigen-expressing B-cell lymphoma cells. Methods: Pts with sWM received 3 i.d. vaccinations of pt-specific DNA vaccine at 4-week (wk) intervals (wks 0, 4 and 8). Two dose levels (500µg; 2500µg) were evaluated in a 3+3 design. Primary objective: to evaluate the vaccine’s safety and identify it’s MTD. Secondary objectives: 1) to assess immunogenicity of the vaccine 2) to determine time to symptomatic WM. Results: Between 1/2016 - 1/2019, 9 pts (7 men) were treated (500 µg: n = 3; 2500µg: n = 6). Median age at enrollment was 67 yrs (range 56-78); median time from diagnosis to 1st vaccination was 26.5 mos (8.8-120.9). MYD88 L265P + (6 pts). CXCR4 WHIM + (1 pt). With median follow up of 26.5 months (range: 8-36.4), all pts remain alive. Seven have stable disease; 2 progressed to symptomatic WM (8 mos. (1pt) and 26 mos. (1pt) from 1st vaccination). All pts completed planned therapy. No DLTs or Grade 4 AEs occurred. Ten mos. after the 3rd vaccination, 1 pt had a grade 3 pleural effusion and leukopenia with an increase in rheumatoid factor (23.1 IU/mL [normal range 0.0-15.9]) and ANA titer of 1:80; all resolved within 2 mos. Grade 1-2 AEs ( > 3pts): leukopenia (6), nausea (5), anemia (4), increased creatinine (4), fatigue (4). Conclusions: Idiotype (scFv-CCL20) DNA vaccine therapy appears to be safe in pts with sWM. Results of immunogenicity assays are underway, and will inform whether tumor specific immune responses are induced. Additional follow up is required to determine time to symptomatic WM. Clinical trial information: NCT01209871.
Initial reporting of NRG-LU001 (NCT02186847), randomized phase II trial of concurrent chemoradiotherapy (CRT) +/- metformin in locally advanced Non-Small Cell Lung Cancer (NSCLC).
Authors: Tsakiridis Theodoros , Hu Chen , Skinner Heath Devin , Santana-Davila Rafael , Lu Bo , Erasmus Jeremy J. , Doemer Anthony , Videtic Gregory M.M. , Coster James , Yang Xuezhong , Lee Richard , Werner-Wasik Maria , Schaner Philip E. , McCormack Steven Eric , Esparaz Benjamin , McGarry Ronald , Bazan Jose G. , Struve Timothy , Bradley Jeffrey D. 
Published: March 2020

8502 Background: Metformin, a diabetes agent that inhibits mitochondria complex I, enhances radiotherapy and chemotherapy responses in pre-clinical models of NSCLC. NRG-LU001 examined whether metformin can improve outcomes of curative CRT in locally advanced (LA)-NSCLC. Methods: The primary endpoint of this trial was 1-year progression free survival (PFS). Unresected, non-diabetic, stage IIIA/B NSCLC patients were randomized (1:1) to either carboplatin-paclitaxel chemotherapy concurrent with chest RT (60Gy), followed by consolidation carboplatin-paclitaxel chemotherapy (Control Arm) or the same and oral metformin (2000mg daily) during cytotoxic therapy (Experimental Arm). PFS and overall survival (OS) were estimated with the Kaplan-Meier method; time to local-regional progression (TTLRP), time to distant metastasis (TTDM) were estimated using the cumulative incidence method. Adverse events (AEs) were graded with CTCAE v.4.0. Results: Between Aug.2014 and Dec.2016, 170 patients were accrued. Analysis was planned at 102 PFS events (Feb. 2019). There was no significant difference in rates or grade of toxicity between the two arms. 1- and 2-year PFS was 60.4% (95% CI: 48.5, 70.4) and 40.1% (95% CI: 29.0, 51.0) in Control vs 51.3% (95% CI: 39.8, 61.7) and 34.5% (95% CI: 24.2, 45.1) in the Metformin arm (multivariable Cox proportional HR=1.20 (95% CI: 0.81, 1.78), p=0.36). OS at 2 years was 65.4% (95% CI: 53.5, 75.0) for Control vs 64.9% (95% CI: 53.1, 74.5) for the Metformin arm (HR=1.03 (95% CI: 0.64, 1.68)), while deaths due to disease were 90% vs 71%, respectively. No significant differences were found for TTLRP or TTDM. Conclusions: NRG-LU001 center reported outcomes show that oral daily metformin was well-tolerated in combination with CRT treatment for LA-NSCLC. However, metformin did not improve PFS and OS and did not alter the rates of local-regional failure or distant metastasis. Acknowledgements: TT and HS are Co-Principal Investigators. This project was supported by National Cancer Institute (NCI) grants: U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC). Clinical trial information: NCT02186847.