bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment patterns for extramedullary multiple myeloma and outcomes with CAR-T therapy and bispecific antibodies.
Authors: Zanwar Saurabh , Ho Matthew , Kapoor Prashant , Binder Moritz , Buadi Francis , Dispenzieri Angela , Dingli David , Fonder Amie L. , Gertz Morie A. , Gonsalves Wilson I. , Hayman Suzanne R. , Hwa Yi Lisa , Hobbs Miriam A. , Kourelis Taxiarchis , Lacy Martha , Leung Nelson , Muchtar Eli , Warsame Rahma M. , Rajkumar S. Vincent , Kumar Shaji 
Published: June 2023

8022 Background: Extramedullary Multiple Myeloma (EMM) is an aggressive entity with a dismal prognosis. Immune effector therapies (IETs), including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific T-cell engaging antibodies (BsAb), have demonstrated excellent efficacy in relapsed/refractory MM with limited data for efficacy in EMM. Here, we report the treatment outcomes for patients with EMM. Methods: We identified 299 patients with EMM diagnosed between 01/01/2000 and 12/31/2021 after excluding solitary plasmacytomas, paraskeletal MM and primary plasma cell leukemia. The IMWG criteria were used for response definition. Results: Of the 299 patients, 204 (68%) patients had secondary EMM (sEMM) and 95 (32%) patients had primary EMM (pEMM). For sEMM (n=204), the median progression free survival (PFS) with initial therapy was 2.9 (95% CI: 2.4-3.2) months. Initial treatment strategies for sEMM were heterogenous and demonstrated in the table; 44% patients achieved ≥partial response (PR) with initial treatment for sEMM. The median PFS in patients with ≥PR was 5.8 (95%CI: 4.5-6.9) months vs 1.8 (95%CI: 1.4-2; p <0.0001) months for <PR. For patients with pEMM (n=95), the median PFS was 12.9 (95% CI: 6.7-18) months; the median PFS was 17.4 (95%CI: 12.9-25.4) months for patients with ≥PR versus 1 month (95%CI: 0.8-2) in patients with <PR. Thirty patients (all sEMM and triple class refractory) were treated with IET after development of EMM: 18 with BCMA-directed CAR-T, 10 with BsAbs, and 2 with both CAR-T and BsAbs. In patients receiving CAR-T therapy, 75% (15/20) achieved ≥PR with 40% (n=8) achieving MRD negative (by flowcytometry) complete response. Fifteen (75%) patients receiving CAR-T had progressive disease (PD); 7 with systemic and EMM PD and 4 patients each with isolated EMM or systemic PD. The median PFS for patients treated with CAR-T was 4.9 months [3.1- not reached (NR)]. Among patients achieving a ≥PR with CAR-T, the median PFS was 5.8 (95%CI: 4.7-NR) months vs 1.4 months [(95%CI: 0.8-NR), p<0.001] for <PR. Among patients treated with BsAbs (10-BCMA, 1 each against FcRH5 and GPRC5D), 33% (4/12) achieved a ≥PR. Ten (83%) patients had PD on BsAb; 8 with both EMM and systemic PD and 1 patient each with isolated EMM or PD. The median PFS with BsAb was 2.9 months (95%CI: 2.2-NR). Conclusions: Patients with EMM continue to have dismal outcomes with conventional therapies. High response rates were noted with CAR-T therapy, but these tend to be short-lived. [Table: see text]
Durability of responses with biweekly dosing of teclistamab in patients with relapsed/refractory multiple myeloma achieving a clinical response in the majesTEC-1 study.
Authors: Usmani Saad Zafar , Karlin Lionel , Benboubker Lotfi , Nahi Hareth , San-Miguel Jesús , Trancucci Danielle , Qi Keqin , Stephenson Tara , Perales-Puchalt Alfredo , Chastain Katherine , Chari Ajai 
Published: June 2023

8034 Background: Teclistamab is the first B-cell maturation antigen (BCMA) bispecific antibody approved for the treatment of relapsed/refractory multiple myeloma (RRMM) at a dose of 1.5 mg/kg weekly (QW) given subcutaneously. A less frequent dosing schedule offers added convenience and flexibility to patients, physicians, and caregivers. We evaluated the ability of patients to maintain their responses after transitioning from QW to every other week (Q2W) dosing schedules in the pivotal phase 1/2 MajesTEC-1 trial (NCT03145181/NCT04557098). Methods: Eligible patients had RRMM and received ≥3 prior lines of therapy including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. Prior BCMA-targeted therapy was not allowed in this cohort. Patients received the recommended phase 2 dose (RP2D) of 1.5 mg/kg teclistamab QW, with the option to switch to Q2W dosing if patients achieved a confirmed partial response or better after ≥4 cycles of treatment (phase 1) or a confirmed complete response (CR) or better for ≥6 months (phase 2). Response was assessed per IMWG 2016 criteria. Results: As of Dec 9, 2022, 165 patients in the pivotal cohort had received teclistamab at the RP2D. Of 104 responders, 60 patients switched to Q2W dosing; 50 met the protocol-defined criteria for switching, and 10 switched who did not meet the criteria (4 due to adverse events [AEs]; 6 due to other reasons). Patients who switched had a median age of 64 years, 58% were male, 25% had high-risk cytogenetics, 7% had extramedullary plasmacytomas, and 3% had International Staging System stage III disease at baseline. Patients received a median of 4 prior lines of therapy, and 75% were triple-class refractory. At the time of switch, 49 (82%) patients achieved ≥CR, and 11 (18%) had a very good partial response. Median time to switch from QW to Q2W dosing was 11.1 months (range, 3–20). At median 11.1-month (range, 2–24) follow-up since switching, the median duration of response from the date of switch was 20.5 months (range, 1–23), with 40/60 patients still in response and ongoing treatment. Of the remaining patients, 13/60 have progressed (median time from switch to progression not estimable), 2 discontinued due to AEs, 1 discontinued for other reason, and 4 died. Additional results will be presented. Conclusions: Overall, patients from the MajesTEC-1 study who transitioned from QW to less frequent Q2W dosing of teclistamab had sustained remission, with a median duration of response of 20.5 months from the date of switch. Clinical trial information: NCT03145181 , NCT04557098 .
Adjusted indirect treatment comparison of progression-free survival (PFS) associated with DRd and VRd based on MAIA and SWOG S0777 individual patient-level data.
Authors: Durie Brian G. , Kumar Shaji , Ammann Eric M. , Fu Alex Z. , Kaila Shuchita , Lam Annette , Usmani Saad Zafar , Facon Thierry 
Published: June 2023

8037 Background: Both daratumumab in combination with lenalidomide and dexamethasone (DRd) and bortezomib in combination with lenalidomide and dexamethasone (VRd) are endorsed by NCCN guidelines as preferred regimens for the treatment of transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). DRd and VRd have each demonstrated superior efficacy relative to lenalidomide and dexamethasone (Rd) alone in the MAIA and SWOG S0777 trials, respectively, but have not been compared directly in a head-to-head trial. Naive comparisons of efficacy across the 2 trials may be biased because MAIA enrolled only TIE patients (median age 73 years), whereas S0777 enrolled a mixed transplant-not-intended (TNI) population, which included both TIE patients and patients choosing to defer/refuse frontline stem cell transplantation (median age 63 years). Methods: The present study leveraged individual patient-level data (IPD) from both trials to perform an anchored indirect treatment comparison of DRd vs VRd, adjusting for differences in trial eligibility criteria and baseline patient characteristics. Harmonized inclusion criteria (NDMM, age ≥65 years, ECOG performance status ≤2) were applied to both trial populations. Age ≥65 years served as a proxy for TIE status since S0777 enrolled a mixed TNI population. Propensity score (PS) reweighting was used to balance the 2 trial populations on key baseline prognostic factors including age, sex, ISS stage, ECOG performance status, hemoglobin, eGFR, lactate dehydrogenase (LDH) level, and cytogenetic risk. Missing data were addressed with multiple imputation. After alignment of inclusion criteria and PS reweighting, an anchored indirect comparison was performed wherein within-trial progression-free survival (PFS) hazard ratios (HRs) for DRd vs Rd and VRd vs Rd were estimated and used to make indirect inference about PFS for DRd vs VRd. Results: 727 MAIA participants and 198 S0777 participants were eligible for inclusion. After PS reweighting, the trial populations were balanced on the key baseline prognostic factors identified above (standardized difference < 0.1 for each). The adjusted PFS HRs were 0.53 (95% CI: 0.41–0.68; P< 0.0001) for DRd vs Rd in MAIA and 0.88 (0.63–1.23; P= 0.46) for VRd vs Rd in S0777. In the adjusted Rd-anchored indirect comparison, the PFS HR for DRd vs VRd was 0.60 (0.39–0.90; P= 0.02). Conclusions: In this adjusted indirect treatment comparison based on IPD from the MAIA and S0777 trials, PFS was significantly longer for DRd relative to VRd. In the absence of a head-to-head trial comparing DRd and VRd, the present study may help to inform treatment selection in TIE patients with NDMM.
Results from a first-in-human phase I study of F182112, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma.
Authors: Sun Mingyuan , Qiu Lugui , Wei Yongqiang , Jin Jie , Li Xin , Liu Xue , Yin Shaohong , Qi Junyuan 
Published: June 2023

8038 Background: F182112 is a BCMA x CD3 bispecific antibody that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing myeloma cells.NTP-F182112-001 is a First-in-human, Open-label, Multiple center Phase 1 Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetic, Immunogenicity, and Preliminary Efficacy of F182112 in Patients with Relapsed or Refractory Multiple Myeloma. Clinical trial information: NCT04984434. Methods: Eligible patients aged ≥ 18 years had received at least 2 prior multiple myeloma treatment regimens (not including autologous stem cell transplant) including a proteasome inhibitor, an immunomodulatory agent. Three dose cohorts (0.01, 0.1, and 0.3μg/kg) were planned for accelerated titration phase and the following dose cohorts (3, 10,20, and 30 μg/kg) were planed for the i3+3 dose escalation phase. F182112 were administered as QW or Q2W IV infusion. The primary endpoint was safety and tolerability assessed throughout the study by monitoring AEs per the CTCAE 5.0, except CRS per ASTCT 2018. Results: As of Feb 2,2023, 16 pts in the first 7 cohorts received F182112 (0.01-20 μg/kg). Median follow-up was 3.1 mo (range 0.9–11.7; median age 64 y [range 52–74]; 68% female). 9 (56%) pts had received ≥4 prior lines of therapy and 12 (75%) pts were refractory to last lines of therapy. The ORR was 43.8% (95% CI 19.8-70.1) among all enrolled patients (7/16). Of the 9 pts treated with ≥ 10 μg/kg F182112, 6 pts achieved a partial response (PR) or better (overall response rate; 66.7%), including 2 (22.2%) with a very good partial response or better.The most common treatment-related AEs were CRS (81%), lymphopenia (75%; grade 3/4: 69%), neutropenia (63%; grade 3/4: 44%), leukopenia (56%; grade 3/4: 50%), and anemia (31%). CRS and anemia events were all grade 1–2 and median duration time to CRS was 2 days (1-5). One dose-limiting toxicities (transient ALT elevation, grade 3) occurred at the dose group of 10 μg/kg. No pts required a F182112 dose reduction due to AEs. Conclusions: F182112 provides a novel immunotherapy approach for the treatment of Relapsed/ Refractory Multiple Myeloma that may yield improved clinical efficacy in heavily pretreated pts. Clinical trial information: NCT04984434.
Identification of cytokines associated with response and cytokine release syndrome: Analysis of MagnetisMM-3 cohort A.
Authors: Quach Hang , Bahlis Nizar J. , Rodríguez-Otero Paula , Viqueira Andrea , Wang Shen-Wu , Sathaiah Sangeetha , Robinson Douglas M , O'Brien Thomas , Weisel Katja 
Published: June 2023

8044 Background: MagnetisMM-3 (NCT04649359) is a phase 2 study of elranatamab monotherapy in patients with multiple myeloma refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Promising efficacy and safety have been observed in patients who were naïve to B-cell maturation antigen (BCMA)-directed therapy (Cohort A) in MagnetisMM-3 (Bahlis et al., ASH 2022). Methods: In MagnetisMM-3, patients received subcutaneous elranatamab in 28-day cycles with step-up doses of 12 mg on C1D1 and 32 mg on C1D4 followed by 76 mg QW beginning C1D8. Serum samples were collected on C1D1 prior to first priming dose, and on C1D2, pre-dose C1D4, C1D5, pre-dose C1D8, C1D15, and C1D22. Levels of 45 peripheral cytokines were analyzed by proximity extension assay and a longitudinal mixed effects model was applied to each cytokine separately. Cytokines with a significant 2-fold differential expression (responders [defined as patients with best overall response of very good partial response or better] vs non-responders [defined as patients with best overall response of partial response or worse]; cytokine release syndrome [CRS] vs no CRS) at any timepoint are reported. Clinical data cutoff was in Oct 2022 with median follow up of 10.4 months. Results: Baseline levels of IL-6 (2.6-fold), IL-17C (2.0-fold), and MIP-1α (2.1-fold) were lower in patients who achieved a response. After the first priming dose, 13 cytokines in the panel, including CCL8, IFN-γ, IL-2, and IL-27, were differentially expressed in responders vs non-responders. At baseline, no cytokines were found to predict CRS. After the first priming dose, 18 cytokines in the panel, including CCL8, IFN-γ, IL-10, IL-2, IL-27, IL-6, and IL-17A, were differentially expressed in patients with CRS vs no CRS. The maximal differential expression for 17/18 cytokines occurred at C1D2, ~24 hours post the first priming dose. Conclusions: Lower baseline levels of IL-6, IL-17C, and MIP-1α correlated with a response of VGPR or better in BCMA-naïve patients from MagnetisMM-3, suggesting that lower levels of these cytokines might reflect a favorable immune environment. Many cytokines were differentially expressed at higher levels in patients who experienced CRS vs those who did not; the most prominent cytokines included CCL-8, IFN-γ, and IL-10. The timing of induction of CCL-8, IFN-γ, and IL-10 occurred by C1D2 suggesting a potential contribution of these cytokines in driving CRS. Clinical trial information: NCT04649359 .
Three-dimensional telomere profiling to predict risk of progression in smoldering multiple myeloma.
Authors: Kumar Shaji , Rajkumar S. Vincent , Jevremovic Dragan , Kyle Robert A. , Mai Sabine , Louis Sherif 
Published: June 2023

8056 Background: Multiple myeloma (MM) is preceded by monoclonal gammopathy of undetermined significance (MGUS). A transitional stage of smoldering multiple myeloma (SMM) can be identified between MGUS and MM. While MGUS carries a steady risk of progression of 1% per year, SMM is more heterogenous with nearly 40% of patients progressing in the first 5 years, 15% in the next 5 years, reaching the same low risk as MGUS after 10 years. SMM with its high risk of progression in the initial years after diagnosis presents a viable opportunity for early intervention. For implementing early intervention, the ability to identify SMM patients at the highest risk of progression is critical. This has led to the development of several risk stratification systems. Using these systems high risk SMM patients studied in phase 3 trials demonstrated delayed progression to MM and improved overall survival with early initiation of therapy. However, these approaches showed limited specificity exposing patients at lower risk of progression to therapy. To date, identifying high risk SMM patients and confirming disease stability in low risk SMM patients remain an important clinical need. Genomic instability has been shown to be a sensitive indicator of disease progression in cancer. Telomere dysfunction is an early event in genomic instability. The 3-dimensional spatial profiling of telomeres using TeloView technology allows for quantification of telomere dysfunction, and was shown to be instrumental in risk stratification of cancer patients generally, but particularly in selected hematological malignancies. Importantly, in a previous SMM proof-of-concept study telomeric parameters measured by TeloView technology was found to be significantly different between SMM patients who progressed to active MM within 2 years and those who remained stable for over 5 years. Methods: We analyzed a total of 162 SMM patients using TeloView technology. 88 patients were employed as training dataset in Receiver Operating Curve (ROC) modeling to develop a scoring model that stratifies individual SMM patients based on risk of progression to full stage MM. An additional cohort of 74 SMM patients was used for blind validation of the developed scoring model. Results: We report area-under-the-curve (AUC) in the ROC analysis of 0.8 (accuracy 80%) achieved by the scoring model developed using the training dataset. Furthermore, the independent blind validation achieved positive predictive value of 83% and negative predictive value of 71%, with sensitivity and specificity of 80% and 76% respectively. Conclusions: The result of this study supports presenting TeloView as an accurate prognostic biomarker which appears able to stratify SMM patients into their respective risk groups with high sensitivity and specificity. This will potentially allow for evidence-based treatment decisions for high risk SMM patients and confident monitoring of stable patients.
Genomic landscape of multiple myeloma with extramedullary disease: Results from a large patient database.
Authors: Mejia Saldarriaga Mateo , Jayabalan David , Sowa Aubrie , Monge Jorge , Rosenbaum Cara , Pearse Roger , Niesvizky Ruben , Patel Sajay , Bustoros Mark 
Published: June 2023

8058 Background: Extramedullary disease (EMD) is associated with poor outcomes and the biological mechanisms driving this phenotype are poorly understood. We used the CoMMpass registry data to explore the genomic characteristics of EMD. Methods: The CoMMpass study is a prospective, international registry of newly diagnosed MM. 1143 patients had clinical data. Patients were classified as EMD if they had EMD at any point. Genomic data from bone marrow (BM) samples at diagnosis (whole genome sequencing, whole exome sequencing (WES), and RNA sequencing (RNAseq)) were compared between EMD and non-EMD. A multivariable model was constructed based on univariable results. Differential expression (DEA) and gene set enrichment analysis (GSEA) were performed after normalization using Hallmark and MM transcriptomic subgroups. The top 24 most mutated genes in MM were selected. Results: The median overall survival (mOS) and progression free survival (PFS) was shorter for EMD. The presence of EMD, anemia at diagnosis, age >65 years at diagnosis, ISS stage, and use of ASCT at the first line were independently associated with worse mOS and PFS. EMD was associated with worse mOS (HR 1.7, 95% CI 1.3 - 2.2 p <0.01) and PFS (HR 1.5, 95% CI 1.23 - 1.8, p <0.01) in multivariable analysis and was not abrogated by ASCT, triplet induction or maintenance. Results did not vary when landmark analysis was used. MYC amplification, deletion 18q and 1q amplification were enriched in EMD cases. TP53 mutations and TP53 bi-allelic inactivation (mutation and deletion) were enriched in EMD (Table). DEA identified 1552 genes with increased and 3344 with decreased expression (2.7%, 5.4% of total genes respectively) in EMD when compared to non-EMD. On GSEA, EMD cases were enriched for the CD-1, PR, and CTA myeloma gene expression signatures, in addition to the Hallmark pathways MYC target, E2F targets, G2M checkpoint and unfolded protein response, while the adhesion molecules pathway and MM gene signatures LB, MS, and MF were downregulated in EMD. Conclusions: EMD cases were enriched for TP53 mutations and bi-allelic TP53 inactivation, both of which are prognostic. In addition, MYC amplification, 18q deletion and 1q gain were enriched in EMD which are novel CNA associated with EMD. EMD is also enriched for distinct molecular subgroup, including enrichment for CD-1, PR, and CTA signatures, the latter two are associated with poor outcomes, and the Hallmark pathways MYC, E2F and G2M checkpoints consistent with MYC amplification and PR molecular subgroup. WES and RNAseq of matching BM and EMD tissue samples from our institution is currently being performed. [Table: see text]
Exploratory biomarker analysis of the phase 3 KEYNOTE-604 study of pembrolizumab plus etoposide for extensive-stage SCLC.
Authors: Rudin Charles M. , Kim Hye Ryun , Navarro Alejandro , Gottfried Maya , Peters Solange , Csoszi Tibor , Cheema Parneet Kaur , Rodriguez-Abreu Delvys , Wollner Mira , Yang James Chih-Hsin , Mazieres Julien , Kato Terufumi , Kalemkerian Gregory Peter , Dettman Elisha , Edmondson Mackenzie , Vajdi Amir , Loboda Andrey , El-Osta Hazem Edmond , Zhao Bin , Awad Mark M. 
Published: June 2023

8503 Background: In the phase 3 KEYNOTE-604 study of extensive-stage small-cell lung cancer (ES-SCLC; NCT03066778), first-line pembrolizumab (pembro) plus etoposide and platinum (EP) significantly improved PFS vs placebo (pbo) plus EP (HR, 0.75; P = 0.0023), with favorable OS (significance threshold not met; HR, 0.80; P = 0.0164). PFS/OS were similar regardless of PD-L1 CPS. In this exploratory analysis, tumor mutational burden (TMB), 18-gene T cell–inflamed gene expression profile (TcellinfGEP) and SCLC transcriptional subtypes were assessed as correlates of survival. Methods: Patients (pts) eligible for this analysis of KEYNOTE-604 had previously untreated ES-SCLC with evaluable pretreatment tumor samples. TMB was assessed by whole-exome sequencing (WES) of tumor and matched normal DNA. RNA-seq was used to determine TcellinfGEP and SCLC transcriptional subtypes (ASCL1, POU2F3, NEUROD1, YAP1, or inflamed). Associations of TMB, TcellinfGEP, and SCLC subtype with OS were analyzed using an adjusted Cox proportional hazards model. 1-sided (pembro + EP) and 2-sided (pbo + EP) P values were calculated for TMB and TcellinfGEP (prespecified α = 0.05); 2-sided P values were calculated for SCLC subtype (multiplicity-adjusted, α = 0.10). Clinical utility was assessed using prespecified cutoffs of ≥175 mut/exome for TMB and the first tertile for TcellinfGEP. Clinical data cutoff date was Dec 2, 2019. Results: Of 453 pts randomized in KEYNOTE-604 (ITT), 318 had WES data (pembro + EP, n = 167; pbo + EP, n = 151), and 316 had RNA-seq data (pembro + EP, n = 159; pbo + EP, n = 157). High TMB was positively associated with OS in the pbo + EP group ( P = 0.005) but not the pembro + EP group ( P = 0.450). There was a positive association between higher TcellinfGEP and OS in the pembro + EP ( P = 0.003) and pbo + EP ( P < 0.005) groups. SCLC subtypes were not associated with OS in either group (pembro + EP, P = 0.960; pbo + EP, P = 0.999). Clinical benefit of pembro + EP over pbo + EP was demonstrated for TMB <175 mut/exome, but not for TMB ≥175 mut/exome. Pembro + EP benefit over pbo + EP was consistent across TcellinfGEP subgroups. Conclusions: In this exploratory analysis of biomarker subgroups of KEYNOTE-604, TMB and SCLC subtypes were not associated with OS in the pembro + EP group in pts with ES-SCLC. While TcellinfGEP was positively associated with OS in both treatment groups, no additional OS benefit was observed with pembro + EP. Further research is warranted to better identify predictive biomarkers to immunotherapy. Clinical trial information: NCT03066778 . [Table: see text]