bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA.
Authors: Mateos Maria-Victoria , Nahi Hareth , Legiec Wojciech , Grosicki Sebastian , Vorobyev Vladimir , Spicka Ivan , Hungria Vania TM , Korenkova Sibirina , Bahlis Nizar J. , Flogegard Max , Blade Joan , Moreau Philippe , Kaiser Martin , Iida Shinsuke , Laubach Jacob , Ahmadi Tahamtan , Parasrampuria Dolly A. , Peng Lixian , Qi Ming , Usmani Saad Zafar 
Published: March 2020

8005 Background: In a phase 1b trial, a SC formulation of DARA with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE drug delivery technology, Halozyme, Inc.) had adequate PK, low rates of infusion-related reactions (IRRs) and similar efficacy to DARA IV. This phase 3 study compared the efficacy, PK, and safety of DARA SC vs IV in pts with RRMM. Methods: DARA SC (1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg IV) were given weekly for C1-2 (28-day cycles), every 2 weeks for C3-6, and every 4 weeks thereafter. DARA SC (15 mL) was given over 3-5 mins at alternating left/right abdominal sites. Pts (≥18 years) must have received ≥3 prior lines of therapy (LOT), including a PI and an IMiD, or were double refractory. Co-primary endpoints were ORR (analyzed by Farrington-Manning test, with non-inferiority = 60% retention of ORR) and pre-dose C3D1 DARA Ctrough (non-inferiority = lower bound of 90% CI for the ratio of the geometric means [GM] ≥80%). Results: 522 pts were randomized (n=263 SC; n=259 IV). Median age was 67 yrs. Median baseline body weight was 73 kg. Pts received a median of 4 LOT and 100% had received both PI and IMiD; 17% had high cytogenetic risk at baseline. Median follow-up was 7.5 mos. ORR was 41% for DARA SC and 37% for DARA IV. DARA SC retained at least 89% of the benefit of DARA IV (97.5% confidence). The ratio of GM of Ctrough for DARA SC over DARA IV was 108% (90% CI, 96%-122%). A significantly lower rate of IRRs was observed with DARA SC vs DARA IV (12.7% vs 34.5%; P<0.0001). Median duration of injection was 5 mins for DARA SC and median duration of infusion was 421/255/205 mins for the first/second/subsequent DARA IV infusions. Median PFS was 5.6 mos DARA SC vs 6.1 mos DARA IV (HR, 0.99; 95% CI, 0.78-1.26). Most common TEAEs (≥15%) were anemia, neutropenia, thrombocytopenia, and diarrhea. Primary reasons for treatment discontinuation included progressive disease (43% SC vs 44% IV) and AEs (7% SC vs 8% IV). Conclusions: Efficacy and PK co-primary endpoints were met, demonstrating non-inferiority of DARA SC to IV. DARA SC significantly decreased IRR rate and administration time, with a comparable safety profile to DARA IV. Clinical trial information: NCT03277105.
Combined use of two monoclonal antibodies in patients with systemic AL amyloidosis and cardiac involvement.
Authors: Godara Amandeep , Siddiqui Nauman Saleem , Lee Lisa , Toskic Denis , Fogaren Teresa , Varga Cindy , Comenzo Ray 
Published: March 2020

8009 Background: Systemic AL amyloidosis (AL) is a rare disease in which circulating immunoglobulin light chains misfold, are directly toxic to key organs and also cause organ failure by mass effect. Patients with cardiac involvement have a poor prognosis; 25% of them die within 6 months of diagnosis. Depth of hematologic and organ response has prognostic significance and as new therapies become available, combining targeted therapies might hold the key to improve survival and deepen responses. Methods: We report the outcomes of 9 patients with AL amyloidosis who simultaneously received dual monoclonal antibody therapy with daratumumab and the investigational anti-fibril antibody NEOD001 at our institution. We also provide a descriptive comparison of 10 other AL amyloidosis patients who received treatment with daratumumab alone. Results: Of these 9 patients, there were 4 men/5 women with a median age of 68 years (range, 52-75) and a median of 261 days from diagnosis (range, 51-2037). Median NT-proBNP was 3807 pg/ml (range, 1326-13193). These 9 patients did not respond to initial therapy with a bortezomib-based regimen. Infusions of both monoclonals were separated by 2 days and were well tolerated without any unexpected toxicity. 88% of patients achieved ≥VGPR with daratumumab+NEOD001 in a median of 33 days and cardiac responses were achieved in < 90 days. In contrast, patients receiving daratumumab alone (n=10) achieved hematologic and cardiac responses at later times (Table). Conclusions: In conclusion, dual monoclonal antibodies targeting different epitopes can be safely combined in patients with systemic AL amyloidosis. Although this report features a small number of patients, high rates of hematologic and cardiac responses achieved suggest that this combination should be studied further, possibly in a prospective randomized trial. [Table: see text]
Overall survival (OS) with oral selinexor plus low dose dexamethasone (Sd) in patients with triple class refractory-multiple myeloma (TCR-MM).
Authors: Richardson Paul G. , Jagannath Sundar , Chari Ajai , Vogl Dan T. , Dimopoulos Meletios A. , Moreau Philippe , Dingli David , Wei L J , Li Lingling , Tang Shijie , Reichman William , Kauffman Michael G. , Shah Jatin J. , Shacham Sharon , Lonial Sagar 
Published: March 2020

8014 Background: TCR-MM is defined as being refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 mAbs, representing an urgent unmet medical need with a median OS of 3-5 months( Pick M et al, Eur J Haem 2018; Gandhi U et al, ASH 2018). Sd has shown a 26.2% overall response rate (ORR) in 122 patients (pts) with TCR-MM in the Phase 2b STORM study ( Chari A et al, ASH 2018). Here, we evaluate the OS of pts in the STORM study with Sd and in pts with bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab (“penta”)-exposed, TCR-MM from an observational cohort not receiving Sd. Methods: Data were drawn from STORM and a retrospective cohort from the nationally representative Flatiron Health Analytic Database (FHAD). All pts from both sources had penta-exposed TCR-MM. In order to align study populations, OS was evaluated in pts in STORM whose first therapy after their MM reached TCR status was Sd and in pts in the FHAD who received ≥1 therapy after their MM reached TCR status. The index date for this evaluation was the start date of treatment after their MM reached TCR status. A Cox proportional hazards regression model was performed to assess the survival impact of Sd. In STORM, ORR was assessed by an Independent Review Committee based on IMWG criteria. Results: In the FHAD, 69 pts with TCR-MM were identified. Characteristics of the two groups of pts were similar, except that pts in STORM were more heavily pretreated, had a higher frequency of high-risk MM, a longer time since initial diagnosis of MM, and higher baseline hemoglobin and platelet values. Among the 122 pts in STORM, 64 received Sd as their first therapy after their MM became TCR, and ORR was 32.8%. Among the 69 pts from FHAD, 37 received ≥1 therapy after their MM became TCR. Median OS (N = 64) was 10.4 months for pts receiving Sd in STORM and 5.2 months (N = 37) for pts not receiving Sd in FHAD (HR = 0.49, p = 0.0241). Conclusions: The prognosis of TCR-MM in the real-world population appears very poor. Within the limits of this analysis, median OS of pts receiving Sd as their first therapy after their MM becomes TCR is significantly better than those not receiving Sd, suggesting that Sd may be associated with an OS benefit in pts with TCR-MM. Clinical trial information: NCT02336815.
Faster and sustained improvement in health-related quality of life (HRQoL) for newly diagnosed multiple myeloma (NDMM) patients ineligible for transplant treated with daratumumab, lenalidomide, and dexamethasone (D-Rd) versus Rd alone: MAIA.
Authors: Perrot Aurore , Facon Thierry , Plesner Torben , Usmani Saad Zafar , Kumar Shaji , Bahlis Nizar J. , Ramasamy Karthik , Roussel Murielle , Araujo Carla , Jaccard Arnaud , Delforge Michel , McKay Caroline , Gries Katharine , Trudeau Jeremiah , Hulin Cyrille , Weisel Katja 
Published: March 2020

8016 Background: MAIA, an ongoing phase 3 trial of transplant-ineligible patients (pts) with NDMM, demonstrated significant improvement in progression-free survival with D-Rd vs Rd alone. Assessment of pt-reported outcomes alongside efficacy endpoints provides pt perspective on their quality of survival and overall value of HRQoL while on treatments (tx). Methods: The EORTC QLQ-C30 and EQ-5D-5L questionnaires were completed by pts using an electronic device at baseline and every 3 mo during tx; interim results are presented for first 12 mo. Tx effects were assessed using repeated measures, mixed effects models and thresholds for clinically meaningful benefit were based on established criterion from the literature. Results: Compliance rates were high and comparable at baseline ( > 90%) and through month 12 ( > 80%) for both groups (D-Rd [n = 368]; Rd [n = 369]). Improvement in Global Health Status (GHS) occurred in both groups; however, for D-Rd, significantly greater improvement was observed at cycle 3 (LS mean change; D-Rd: 4.5 [95% CI: 2.4, 6.6], Rd: 1.5 [95% CI: -0.7, 3.7]; [p = 0.0454]) and increasing improvement occurred across all time points. Significant improvement and clinically meaningful benefit in HRQoL for D-Rd was also observed in EQ-5D-5L Visual Analog Scale (VAS) scores (LS mean change; D-Rd: 10.1 [95% CI: 8.1, 12.1], Rd: 4.9 [95% CI: 2.8, 7.0]; [p = 0.0002]). The VAS median time to worsening was 10 mo longer for D-Rd. Of note, meaningful differences were observed between the tx groups in two subscale scores, pain symptoms and cognitive functioning. Statistically significant less pain was reported early with D-Rd (LS mean change at cycle 3; D-Rd: -17.9 [95% CI: -20.7, -15.0], Rd: -11.0 [95% CI: -14.0, -8.1]; [p = 0.0007]); clinically meaningful reduction in pain symptoms was sustained with D-Rd. There was a decline in cognitive functioning at cycle 12 in both tx arms, with no statistically significant differences between groups. Conclusions: Faster and sustained improvement in HRQoL was observed in pts treated with D-Rd vs Rd with similar findings reflected across pain subscale. Clinical trial information: NCT02252172.
Serum BCMA levels to predict outcomes for patients with MGUS and smoldering multiple myeloma (SMM).
Authors: Dispenzieri Angela , Soof Camilia M , Rajkumar S. Vincent , Gertz Morie A. , Kumar Shaji , Bujarski Sean , Kyle Robert A. , Berenson James R. 
Published: March 2020

8020 Background: BCMA (B-cell maturation antigen) is a TNF receptor family member found on normal and malignant B-cells, including multiple myeloma (MM). It plays a role in proliferation and antiapoptotic pathways. Levels of serum (s)BMCA are elevated in patients (pts) with plasma cell disorders (PCD) and increase with each stage of disease: healthy donor< MGUS<SMM< active untreated MM. The purpose of this study was to test whether sBCMA levels predict progression of MGUS or SMM to MM. Methods: There were 3 cohorts in this retrospective study: MGUS progressing to MM (n=42); MGUS not progressing to MM (n=49); SMM progressing to MM (n=32). sBCMA levels were measured using an ELISA-based assay with a polyclonal anti-BCMA antibody from R&D Systems (Minneapolis, MN). The Kruskal-Wallis analysis was used to assess differences. The relationships between sBCMA and both time to progression and overall survival were also assessed using Cox proportional hazard models. Results: The highest values of sBCMA were seen among pts with more advanced PCD (Table). The lowest baseline levels were seen in pts with MGUS who did not progress; the change of sBCMA over time was lowest in the MGUS non-progressors. ROC analysis identified a cutoff of 74.4 ng/mL to be predictive of progression at 5 years. This cut-point was associated with a risk ratio of progression of 5.8 (95%CI 3.2, 11.3) for all comers, a risk ratio of death for all comers of 2.5 (95%CI 1.5, 4.2), and a risk ratio of death for MGUS pts of 3.3 (95%CI 1.9, 5.7). Conclusions: Serum BCMA levels were predictive of diagnosis, progression and death among pts with MGUS or SMM. Limitations of the current study are that only a minority of pts had baseline bone marrow exams or serum FLCs to place sBCMA risk in the context of other previously described risk factors. Serum FLC is now being determined on all patients. [Table: see text]
A health-related quality-of-life (HRQoL) analysis of pomalidomide + low-dose dexamethasone + daratumumab in relapsed refractory multiple myeloma (RRMM) after lenalidomide treatment.
Authors: Reece Donna Ellen , Bahlis Nizar J. , Samaras Christy Joy , Sebag Michael , Berdeja Jesus G. , Ganguly Siddartha , Matous Jeffrey , Song Kevin W. , Seet Christopher , Talamo Giampaolo , Acosta-Rivera Mirelis , Bar Michael , Quick Donald , Anz Bertrand Marquess , Fonseca Gustavo A. , Agarwal Amit , Chung Weiyuan , Zafar Faiza , Siegel David Samuel DiCapua 
Published: March 2020

8025 Background: Treatment (Tx) of RRMM is complex and requires evaluation of disease and patient (pt) factors to maximize efficacy and minimize toxicity. HRQoL has become an important aspect of MM Tx, as survival has improved with therapeutic advances. Results of the ongoing phase 2 MM-014 trial (NCT01946477) have demonstrated that pomalidomide (POM) + low-dose dexamethasone (LoDEX) + daratumumab (DARA) is safe and effective in RRMM pts after first- or second-line lenalidomide (LEN)-based Tx failure. Here we report the impact of this regimen on HRQoL. Methods: RRMM pts with 1 to 2 prior Tx lines, LEN-based Tx as their most recent regimen, and progressive disease during or after their last Tx line received POM + LoDEX + DARA in 28-day cycles (MM-014 cohort B). HRQoL, an exploratory endpoint for cohort B, was assessed via EuroQol’s EQ-5D. Results: As of October 15, 2018, 108 pts were evaluable for HRQoL. Baseline characteristics were similar to those of the ITT population (N = 112). EQ-5D completion rates for each cycle (1-6) were ≥ 88%. Mean change from baseline in the EQ-5D index and VAS health score was stable through 6 Tx cycles. At cycle 6, 28.8% and 39.0% of pts achieved minimum clinically important improvement in the EQ-5D index (≥ 0.1) and VAS health score (≥ 6), respectively. EQ-5D index values were stable, with a trend toward improvement in usual activities, pain/discomfort, and anxiety/depression (Table). Conclusions: In RRMM pts with early-line LEN Tx failure, HRQoL was maintained or trended toward improvement with POM + LoDEX + DARA, despite the combination of 3 drugs with distinct toxicities. These findings further support the earlier use of POM-based Tx in RRMM immediately after LEN failure. Clinical trial information: NCT01946477. [Table: see text]
Minimal residual disease clinical monitoring and depth of response in multiple myeloma.
Authors: Martinez-Lopez Joaquin , Wong Sandy Wai Kuan , Shah Nina , Bahri Natasha , Zhou Kaili , Martin Thomas G. , Wolf Jeffrey Lee 
Published: March 2020

8026 Background: MRD assessment is a known surrogate marker for survival in multiple myeloma (MM). Most data come from patients enrolled in clinical trials. We present a single institution’s experience assessing MRD in patients receiving frontline therapy and therapy for relapsed disease. We describe the impact of depth, duration, and direction of response on prognosis. Methods: 181 MM patients at University of California, San Francisco (UCSF) from 2008 to 2016. 126 were newly diagnosed and 55 in ≥ 2nd line. MRD was assessed in patients achieving VGPR or better by IMWG criteria. MRD assessment was performed by NGS (Adaptive Biotechnologies, Seattle, WA). PFS curves were plotted by the Kaplan-Meier method, and the log-rank test was used to estimate statistical significance. Results: 398 MRD samples were analyzed. MRD was available at 3 time points for 59 patients and 2 time points for 36 patients. Median follow up was 26m. Overall, 66 of 181 patients (36%)achieved MRD- ( < 10-6) on one or more samples. In the newly diagnosed group, 43 of 126 (34%), achieved MRD- at least once. These patients had a prolonged PFS versus patients who were persistently MRD+ (NR vs 49m, p = 0.006). Of the 55 patients who received therapy for relapsed disease, 21 achieved MRD- (38%) and PFS was also prolonged versus patients who remained MRD+ (53m vs 23m, p = 0.03). We analyzed the effects of depth of response. Patients who were MRD- or who were MRD+, at a very low level (between 10-5and 10-6), had a better prognosis than those with higher disease burdens ( > 10-5) (p = 0.001). Finally, we analyzed the effect of repeated MRD monitoring on PFS. Three categories were identified in newly diagnosed patients: (A) patients with ≥3 MRD- samples, (B) patients with continuously declining detectable clones, and (C) patients with a stable number of clones. Groups A and B had a more prolonged PFS than group C (NR vs 31m, p < 0.0001). Conclusions: MRD assessment in a real-world setting has the same predictive power as that seen in clinical trials. MRD dynamics can accurately predict disease evolution and drive clinical decision-making. This study lends support to the concept of MRD-driven decision-making and helps validate the relevance of MRD.
Carfilzomib (K) in relapsed and refractory multiple myeloma (RRMM): Frailty subgroup analysis from phase III ASPIRE and ENDEAVOR.
Authors: Facon Thierry , Niesvizky Ruben , Weisel Katja , Bringhen Sara , Ho P. Joy , Obreja Mihaela , Yang Zhao , Klippel Zandra Karina , Blaedel Julie , Mezzi Khalid , Siegel David Samuel DiCapua 
Published: March 2020

8028 Background: K-based regimens improved progression-free survival (PFS) and overall survival (OS) in RRMM patients (pts) in ASPIRE (K [27 mg/m2]-lenalidomide-dexamethasone [KRd] vs Rd) and ENDEAVOR (K [56 mg/m2]-dexamethasone [Kd56] vs bortezomib-dexamethasone [Vd]), regardless of age. Frailty scores have been developed based on age, comorbidities, and functional status (Palumbo Blood 2015;125:2068–74; Facon Blood 2015;126:4239). We assessed post hoc pt outcomes by frailty status. Methods: PFS, OS, and safety were assessed by treatment arm and frailty score (based on age, medical history-derived Charlson Comorbidity Index, and ECOG performance status); frailty scores: 0 = fit, 1 = intermediate (int), and ≥2 = frail. Results: Pt frailty status was balanced between treatment arms in ASPIRE and ENDEAVOR. Median PFS and OS were longer with K-based regimens vs controls in ASPIRE and ENDEAVOR across frailty subgroups (Table). Rates of treatment-emergent adverse events are summarized in the Table. Conclusions: Kd56 and KRd consistently improved outcomes vs Vd and Rd, respectively, in all frailty subgroups as defined by the algorithm above. These findings support the favorable benefit-risk profile of KRd and Kd56 regardless of frailty score. Clinical trial information: NCT01080391 and NCT01568866. [Table: see text]
Effect of t(11;14) on outcomes of patients (pts) with newly diagnosed multiple myeloma (NDMM) in the connect MM registry.
Authors: Gasparetto Cristina , Jagannath Sundar , Rifkin Robert M. , Durie Brian G. , Narang Mohit , Terebelo Howard R. , Toomey Kathleen , Hardin James W. , Wagner Lynne I. , Ailawadhi Sikander , Omel James , Lee Hans Chulhee , Srinivasan Shankar , Dhalla Mazaher , Catamero Donna , Agarwal Amit , Abonour Rafat 
Published: March 2020

8032 Background: The impact of t(11;14) (16%–24% of MM pts) on prognosis is not fully understood. Consensus is lacking on the effects of induction treatment (tx) on outcomes with t(11;14). The Connect MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with NDMM designed to examine real-world diagnostic patterns, treatment (tx) patterns, clinical outcomes, and HRQoL pt-reported outcomes in pts with NDMM. The impact of t(11;14) on tx outcomes are reported. Methods: Analysis included data from pts from 250 community, academic, and government sites in cohort (C) 1 (9/2009–12/2011) and C2 (12/2012–4/2016), who completed first-line (1L; induction) tx and were tested for t(11;14) by FISH or cytogenetics. Primary end points (progression-free survival [PFS] and overall survival [OS]) were measured from start of 1L tx to earliest event (PFS, death or progression; OS, death), loss to follow-up, or data cutoff, adjusted for baseline (BL) risk factors. A sensitivity analysis excluding pts with concomitant cytogenetic abnormalities [del 17p, t(4;14), t(14;16), 1q+] was also performed. Results: By 1/2018, 3011 pts were enrolled; 2938 were treated. Of 1574 enrolled pts tested for t(11;14), 378 were t(11;14)+ and 1196 were t(11;14)−. More pts in C2 vs C1 were t(11;14)+ (60% vs 40%). BL characteristics were similar between groups. t(11;14) status did not affect PFS ( P= NS) or OS ( P= NS; Table). Pts in C1 and C2 received similar 1L txs (IMiD agent + proteasome inhibitor [PI], 30% vs 42%; PI only, 42% vs 43%; IMiD agent only, 17% vs 11%). Results were similar when pts with concomitant abnormalities were excluded. Conclusions: Results of this analysis suggest that t(11;14) does not affect PFS and OS outcomes in NDMM pts. Clinical trial information: NCT01081028. [Table: see text]
Efficacy and safety of daratumumab, bortezomib, and dexamethasone (D-Vd) in relapsed or refractory multiple myeloma (RRMM) based on cytogenetic risk: Updated subgroup analysis of CASTOR.
Authors: Weisel Katja , Spencer Andrew , Lentzsch Suzanne , Avet-Loiseau Herve , Mark Tomer M. , Spicka Ivan , Bosi Alberto , Hungria Vania TM , Cavo Michele , Lee Je-Jung , Nooka Ajay K. , Quach Hang , Munder Markus , Beksac Meral , Sonneveld Pieter , Soong David , Ukropec Jon , Qi Ming , Mateos Maria-Victoria 
Published: March 2020

8040 Background: MM patients (pts) with high cytogenetic risk have poor outcomes. In CASTOR, D-Vd prolonged progression-free survival (PFS) vs bortezomib and dexamethasone (Vd) alone, and exhibited tolerability in RRMM pts. We conducted a subgroup analysis of D-Vd vs Vd in CASTOR, based on cytogenetic risk. Methods: Pts received ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of next-generation sequencing (NGS) and fluorescence in situ hybridization/karyotype testing. High-risk pts had t(4;14), t(14;16), or del17p abnormalities. Standard (std)-risk pts were confirmed negative for all 3 abnormalities. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ assay V2.0. Results: In CASTOR (D-Vd, n = 251; Vd, n = 247), high-risk was confirmed in 26.7% and 25.9% of pts in the D-Vd and Vd groups, respectively. At a median follow up of 40.0 months (mo), D-Vd prolonged PFS vs Vd in pts with high- (median 13.4 vs 7.2 mo; HR, 0.40 [95% CI, 0.24-0.65]; P = 0.0002) or std-risk (median 18.4 vs 6.8 mo; HR, 0.28 [95% CI, 0.20-0.37]; P < 0.0001). Higher rates of ORR, MRD negativity, and sustained MRD negativity were seen with D-Vd vs Vd (Table). D-Vd prolonged PFS in first relapse pts (high risk: median 20.1 vs 8.4 mo; HR, 0.30 [95% CI, 0.14-0.64]; P = 0.0012; std risk: median 32.6 vs 7.9 mo; HR, 0.18 [95% CI, 0.11-0.29]; P < 0.0001) and PFS2 vs Vd (high risk: median 27.9 vs 18.6 mo; HR, 0.59 [95% CI, 0.37-0.94]; P = 0.0258; std risk: median 40.1 vs 21.6 mo; HR, 0.43 [95% CI, 0.32-0.59]; P < 0.0001) regardless of risk. Additional data will be presented. Conclusions: Adding daratumumab to Vd demonstrates significant efficacy in high-risk RRMM. Among high-risk pts, MRD negativity was only achieved with D-Vd. These findings support use of D-Vd for high-risk RRMM. Clinical trial information: NCT02136134. [Table: see text]