bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating CR as a surrogate endpoint for PFS in R/R chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): A meta-analysis of randomized controlled trials (RCT).
Authors: Wang Lin , Disher Tim , Liu Fei Fei , Kurt Murat , Perna Serena K. , Aronitz Elise , Eyre Toby A. , Davids Matthew Steven
Published: June 2024

7046

Background: CLL/SLL is the most common leukemia in adults. Achieving a CR by International Workshop on CLL 2018 criteria indicates complete eradication of CLL/SLL in all disease compartments. Patients with R/R CLL/SLL who achieved CR tend to have delayed disease progression/death compared with patients who did not achieve CR. This is the first report to evaluate CR as a surrogate endpoint for PFS in R/R CLL/SLL using aggregate RCT data. Methods: A systematic literature review (SLR) identified published RCTs in R/R CLL/SLL from inception to 10/2023, reporting nonzero CR rates (CRR) and PFS. Association between treatment effects on CR and PFS across RCTs was estimated using a weighted linear model (WLM) in the primary analysis, and Daniels and Hughes (D&H) and Riley bivariate random-effects meta-analysis (BRMA) in sensitivity analyses. Strength of association was assessed based on surrogacy criteria described by D&H. Predictive performance of models was evaluated using leave-one-out cross-validation. Results: The SLR identified 13 RCTs with a total of 4388 patients with R/R CLL/SLL treated with a variety of therapies, including but not limited to BTKi, BCL2i, PI3Ki, CAR T cell therapy, anti-CD20 mAb, and chemotherapy. Across the evidence base, CRR ranged from 0.48% to 38.10% and median PFS was between 1 and 35.9 months (excluding unreached medians). Across RCTs, contrasting treatment and control arms, higher odds of CR resulted in lower hazards of disease progression/death (CRR improvement translated to PFS benefit). D&H surrogacy criteria were met for WLM: 1) a near-zero, statistically nonsignificant intercept, indicating that no treatment effect on CRR implies no effect on PFS; 2) a negative, statistically significant slope, suggesting that improved CRR correlates with longer PFS; and 3) a near-zero conditional variance, meaning that PFS HR variation was primarily explained by CR odds ratio. During cross-validation, treatment effects on CR were predictive of PFS benefits, as the 95% predictive interval of PFS HR contained the observed HR in all RCTs for WLM. Results were largely consistent across all 3 models(Table). Conclusions: Improved CRR corresponds to prolonged PFS across RCTs and treatment comparisons. The results support CRR as an important treatment goal for R/R CLL/SLL and a valid surrogate endpoint. Consistent results and predictive performance across different models indicate the robustness of the results. [Table: see text]
Association between treatment (tx) response and PFS and OS in R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL): A 12-month landmark (LM) meta-analysis.
Authors: Woyach Jennifer Ann , Wang Xin , Ananthakrishnan Revathi , Ou San-San , Perna Serena K. , Aptekar Jacob , Jain Rahul , Chen Weixi , Ports Kayleen , Ghia Paolo
Published: June 2024

7047

Background: Despite advances in tx for CLL/SLL, CRs are rarely observed after tx in the R/R setting, thus impacting long-term outcomes. We evaluated the association between response after tx and survival outcomes in patients (pt) with R/R CLL/SLL. Methods: Adults with R/R CLL/SLL and ≥ 1 prior line of therapy (LOT) from 6 clinical trials (initiated after 01/01/2012 and completed before 12/31/2022) were sourced from the Medidata Enterprise Data Store. Cox models adjusted for potential prognostic factors were used to assess pt-level associations between achieving and maintaining a CR or CR with incomplete bone marrow recovery (CRi) by 12 mo after start of tx (LM date) and PFS and OS. In separate LM analyses (LMA), associations between achieving and maintaining CR/CRi, PR/nodular PR (nPR) by LM, or non-CR/non-PR (ie, those not achieving or maintaining CR/CRi or PR/nPR or not evaluated by LM), and PFS and OS were assessed. Results: Of 1604 pts (CLL, 97.7%; SLL, 2.3%; age ≥ 65 y, 61.8%; male, 66.6%; ECOG PS 0–1/2, 93.2%/6.8%; median [IQR] follow-up, 3.4 y [2.2–4.1]; median [IQR] LOT, 2 [1–3]; study tx, BTKi [40.4%], BCL2i [40.1%], anti-CD20 mAb [12.5%], and PI3Ki [9.9%]), 15.1% and 61.7% achieved a best overall response of CR/CRi and PR/nPR, respectively (ORR, 76.8%); 6.8% of pts had no response recorded in follow-up. A total of 1178 pts without progression, death, or censoring before LM were included in PFS LMA. Median (95% CI) PFS from LM was 64.4 mo (61.7–not reached [NR]) for CR/CRi, 43.3 mo (38.8–54.7) for PR/nPR, and 23.9 mo (18.3–50.6) for non-CR/non-PR. Pts who achieved and maintained CR/CRi had significantly longer PFS versus both non-CR/CRi and PR/nPR pts, with adjusted HR of 0.62 ( P = 0.01) and 0.64 ( P = 0.02), respectively (Table). For OS LMA, 1404 pts without death or censoring before LM were included. Median (95% CI) OS from LM was NR for CR/CRi and PR/nPR groups and 62.9 mo (51.2–NR) for non-CR/non-PR. At 24 mo from LM, 90% (85%–95%) CR/CRi, 87% (84%–89%) PR/nPR, and 72% (67%–77%) non-CR/non-PR pts were still alive. CR/CRi pts or PR/nPR pts had significantly longer PFS and OS versus non-CR/non-PR pts. Conclusions: We demonstrated that achieving and maintaining CR/CRi by 12 mo after start of tx was associated with significantly improved PFS versus achieving and maintaining PR/nPR, which was also better than not achieving/maintaining any response. These findings support the potential utility of durable CR/CRi as an informative early endpoint for assessing the value of tx in pts with R/R CLL/SLL. Adjusted HR (95% CI) [Table: see text]
Non-Hodgkin lymphoma mortality disparities across different sexes, races, and geographic locations.
Authors: Tan Jia Yi , Yeo Yong Hao , Patel Aharnish , Chan Kok Hoe , Chisti Mohammad Muhsin , Ezekwudo Daniel
Published: June 2024

7063

Background: Non-Hodgkin lymphoma (NHL) is one of the common hematological cancers in the United States (U.S.), accounting for 4% of new cancer cases in 2023. The mortality rate of NHL is the sixth highest among all cancers in the U.S. Our study aimed to examine the trends in NHL mortality and assess the mortality disparities among different sexes, ages, races, geographic locations, and urbanization levels. Methods: Our population-based cross-sectional study analyzed death certificate data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) U.S. from 1999 to 2020 to determine the longitudinal trends of NHL mortality among the U.S. population aged ≥ 15 years. NHL (ICD-10 C82-85) was listed as the underlying cause of death. Age-adjusted mortality rates (AAMRs) per 100,000 individuals were calculated and joinpoint trend analysis were performed to determine the average annual percent change (AAPC) in AAMR trends. Results: From 1999 to 2020, NHL accounted for 457,143 deaths in the United States, of which 54% are men and 46% are women. Excluding unspecified NHL, there were 132,288 (n=132,288/155,957, 84.8%) B cell NHL deaths and 23,669 (n=23,669/155,957, 15.2%) T cell NHL deaths. Overall, the AAMR of NHL decreased from 10.59 (95% CI, 10.46-10.73) in 1999 to 6.21 (95% CI,6.13-6.30) in 2020 with the AAPC of -2.55 (95% CI, -2.63, -2.46). Men had a higher AAMR than women (10.10 [95% CI, 10.06-10.14] vs. 6.29 [95% CI, 6.27-6.32]). Non-Hispanic Whites recorded the highest AAMR (8.43 [95% CI, 8.40-8.45]), followed by non-Hispanic Blacks (5.71 [95% CI, 5.64-5.77]), Hispanics (6.32 [95% CI, 6.25 - 6.40]), American Indians (5.31 [95% CI, 5.04 - 5.58]), and Asians (5.10 [95% CI, 5.00 - 5.19]). Death from NHL was the most common in patients aged 75 years and above (52.50%), followed by patients aged 55-74 years (37.49%) and patients aged 15-54 years (10.41%). Those who lived in the Midwest region had the highest AAMR (8.60 [95% CI, 8.55-8.65], followed by the Northeast region (7.99 [95% CI, 7.94 - 8.05]), the South region (7.73 [95% CI, 7.70 - 7.77]), and the West region (7.58 [95% CI, 7.54 - 7.63]) . The rural population has a higher AAMR compared to the urban population (8.35 [95% CI, 8.29-8.41] vs. 7.86 [95% CI, 7.83 - 7.88]). Conclusions: NHL mortality has declined over the last two decades. The higher mortality rates existed among men, non-Hispanic White individuals, and the rural population warrant targeted intervention to address the mortality disparities.
Clinical and financial burden of mental health (MH) conditions in patients (pts) with low-grade non-Hodgkin lymphoma (LG-NHL).
Authors: Yang Keri , Esselman Kaitlyn , Chuang Po-Ya , Furnback Wesley , Chanan-Khan Asher Alban Akmal
Published: June 2024

7072

Background: LG-NHL is mostly incurable, imposing a prolong impact of cancer care burden for pts. This study aimed to quantify the burden of MH conditions in pts with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), or marginal cell lymphoma (MZL). Methods: A retrospective study was conducted using Optum Clinformatics Data Mart to identify pts ≥18 years with ≥1 new diagnosis for CLL, FL, MCL, WM, or MZL from 6/2016-6/2022 (index period). Pts were required to be continuously enrolled for 60 days pre- and 365 days post-index date, defined as the date of first cancer diagnosis. Incidence and prevalence of MH conditions of interest (anxiety, depression, stress reaction/adjustment disorder, insomnia, post-traumatic stress disorder [PTSD]) were categorized based on if diagnoses were post- or pre-index date. All-cause healthcare resource utilization (HCRU) and costs were measured during the 1-yr follow-up period. Results: Approximately half of newly diagnosed 36,054 LG-NHL pts (CLL/SLL=48.0%; FL=52.7%; MCL=57.2%; WM=50.5%; MZL=52.5%) had either an incident (19.4-25.7%) or prevalent (28.6-32.1%) MH condition diagnosis following their cancer diagnosis (Table). There were no significant demographic differences in pts with and without MH conditions. LG-NHL pts suffered most from anxiety (30.9-38.2%) and depression (27.5-31.9%), followed by insomnia (16-23.1%), stress (10.3-13.5%), and PTSD (1.4-1.9%). Median time from cancer diagnosis to onset of a MH condition was 334 days for CLL/SLL, 301 for FL, 248 for MCL, 351 for WM, and 328 for MZL. LG-NHL pts with an identifiable MH diagnosis had significantly higher costs and HCRU compared to those without; for example, in CLL/SLL pts with MH diagnosis, outpatient visits were 1.4 times higher, inpatient admissions 3.0 times higher, and costs 2.1 times higher than those without (all P=0.0001). HCRU and cost increases were also observed in MCL, FL, WM, and MZL pts with MH diagnosis. Conclusions: This real-world study uncovered a high proportion of LG-NHL patients suffer from MH conditions, incurring higher financial burden than those without. With advancements in new treatments, there remains unmet need of MH burden in these pts. [Table: see text]
Survival outcomes after autologous stem cell transplantation in T follicular helper type lymphoma.
Authors: Lionel Anath Christopher , Elias Alexandra , Prakash Rishab , Vega Francisco , Patel Keyur P. , Hosing Chitra M. , Malpica Luis , Nair Ranjit , Srour Samer Ali , Iyer Swaminathan Padmanabhan
Published: June 2024

7073

Background: T follicular helper (TfH)-type lymphoma is the most common subtype of peripheral T-cell lymphoma (PTCL). TfH lymphoma consists of angioimmunoblastic T-cell lymphoma (AITL), PTCL-TfH and Follicular T cell lymphoma. Most patients receive first-line treatment with anthracycline-based chemotherapy regimens with a potential role for consolidation with autologous stem cell transplantation (ASCT). In this study we analyzed survival outcomes in TfH lymphoma. Methods: This is an IRB approved retrospective analysis of patients with TfH lymphoma followed between 1997–2023 at the MD Anderson Cancer Center. Demographics, treatment history, response and survival outcomes were collected and analyzed. Next-generation sequencing (NGS) data was collected from a panel of 162 cancer-related genes. Survival analysis was performed with Kaplan Meier curves and comparisons were made with log-rank tests. Results: Of the 218 patients with TfH lymphoma for whom information was known about prior history of ASCT, 84 (39%) underwent ASCT (Table). At the time of diagnosis, the majority of patients had advanced stage disease (92% with stage III or IV) and elevated LDH (89%). NGS testing was available from 31 patients and the genes with recurrent somatic mutations identified were TET2 (65% patients), DNMT3A (29%), RHOA (13%), IDH2 (10%), PLCG1 (10%), TP53 (10%), ATM (6%), CCR7 (6%), JAK3 (6%) and STAT3 (6%). The three most common first-line treatments were CHOP (37%) followed by CHOEP (14%) and combination of brentuximab with either CHP or CHEP (13%). Patients who received ASCT were significantly younger (Table). The median overall survival (OS) for the cohort was 40.3 months with median progression-free survival (PFS) after first treatment of 12.5 months. Patients who received ASCT had a significantly higher overall survival (log-rank test p-value < 0.01) compared to those who did not receive ASCT. Conclusions: This retrospective analysis of a large single institution cohort of patients with TfH lymphoma found significantly improved OS in those who underwent ASCT compared to those who did not. Given the sizeable proportion of patients who are transplant-ineligible due to age or comorbidities, there is a need for newer consolidation approaches for TfH lymphoma. [Table: see text]
Exploring the role of the combination of FDG PET plus whole body MRI for staging newly diagnosed and relapsed/refractory multiple myeloma: A prospective trial.
Authors: Cerchione Claudio , Nappi Davide , Marchesini Matteo , Cangini Delia , Ronconi Sonia , Ceccolini Michela , Prochowski Iamurri Andrea , Matteucci Federica , Simonetti Giorgia , Musuraca Gerardo , Martinelli Giovanni , Rossi Alice
Published: June 2024

7512

Background: The integration of FDG-PET/TC and WB-MRI in the diagnosis of MM may results in higher accuracy to detect bone lesion compared to them alone. This could be translated into better outcomes if early detection of myeloma defining events leads to earlier induction or re-induction treatments. Methods: In our Institution, from January 2021 to January 2023, we performed a prospective trial enrolling 73 consecutive newly diagnosed and relapsed/refractory MM (median age 63 years - range 85-35), according to IMWG, in which WB-MRI was performed according to MY-RADS criteria in combination with FDG PET/CT. 31/73 (42%) had a newly diagnosed MM, 25/73 (34%) were in follow-up after autologous stem cell transplantation and 17/73 (23%) patients were affected by relapsed/refractory MM. Subsequently, in 2 cases WB-MRI were aborted and not diagnostic so patients were excluded from the final analysis. Results: In these 71 patients: 52/71 (73%) cases of concordance of WB-MRI and 18F PET-CT, 18/71 (25%) cases of discordance. In this group 15/18 (83%) cases FDG-PET/CT was negative and WB-MRI showed positive findings according to MYRADS criteria (5 micronodular pattern, 9 diffuse pattern e 1 focal pattern) (Figure 1 Newly diagnosed MM – diffuse pattern in WB-MRI, PET negativity), in 3/18 (17%) FDG-PET/CT was positive for focal lesions and WB-MRI was negative. IMWG criteria showed concordance with WB-MRI data in 16/18 (89 %), in 2/18 (11%) case of follow-up after autologous stem cell transplantation PET-CT showed a relapsed focal lesion while WB-MRI was negative. Accuracy of WB-MRI was 69/71 (97%), whilst PET-CT was 55/71 (77%). These results are in agreement with the literature data about the ability of WB-MRI to depict diffuse and micronodular pattern of bone marrow infiltration. Conclusions: Our preliminary results support a potential complementary role of WB-MRI and FDG PET/CT findings, on the management of patients with MM at both diagnosis and relapse. To date, there is no wide availability of WB-MRI because in concerning about costs and technical issues, but data are consistent with its possible future leading role in MM diagnostic work-up.
Expression of alternatively spliced BCMA RNA with skipping of transmembrane domain.
Authors: Ip Andrew , Albitar Maher , Zhang Hong , Charifa Ahmad , Agersborg Sally , Mohtashamian Arash , Siegel David Samuel DiCapua , Biran Noa , Vesole David H. , Pecora Andrew L , Goy Andre
Published: June 2024

7514

Background: The TNFRSF17 gene, which encodes for the B cell maturation antigen (BCMA), is a small gene expressed mainly on the surface of plasma cells and some DLBCL cells. This gene is composed of three exons. Exon 1 is responsible for the extracellular domain, exon 2 for the transmembrane domain, and exon 3 for the TRAF binding domain. The BCMA is currently targeted by various types of immunotherapies as a major therapeutic approach for the treatment of multiple myeloma (MM). This includes CAR-T cells, bi-specific antibodies, and antibody-drug conjugates (ADC). However, emerging data indicates that alternative splicing in genes is an important mechanism for expression of different isoforms that may influence antibody-based therapies. We explored the potential of the presence of alternative splicing in BCMA transcripts via sequencing of BCMA RNA in patients with lymphoma or multiple myeloma. Methods: RNA was extracted from 587 fresh bone marrow samples with lymphoid/plasma cell neoplasms or from FFPE samples with lymphoma. In addition, cfRNA was extracted from 260 peripheral blood plasma samples from patients with lymphoma or multiple myeloma. RNA was sequenced using a hybrid capture-targeted RNA panel with analysis focused on TNFRSF17 (BCMA) gene transcript. Quantification of RNA transcript was done using Salmon algorithm. Results: Of the 587 lymphoma/plasma cell samples, 161 (27%) samples showed alternative splicing involving deletion of exon 2 (BCMA∆Ex2). Of the 260 cfRNA samples, 14 (6%) showed BCMA∆Ex2. The median percentage of BCMA∆Ex2 transcripts was 0.7% of total BCMA transcripts in cellular samples as compared with 9% in cfRNA samples. In cellular samples, there was a correlation between levels of BCMA and BCMA∆Ex2 (R=0.63). Cases with higher levels of BCMA had significantly higher levels of BCMA∆Ex2 (P<0.0001, Kruskal-Wallis). In contrast, cfRNA showed no correlation between levels of BCMA and levels of BCMA∆Ex2 (R=021, Spearman) and mildly higher level of BCMA∆Ex2 in cases with higher levels of BCMA (P=0.002, Kruskal-Wallis). Conclusions: BCMA exon 2 skipping is detected in a significant number of patients with multiple myeloma and lymphoma. The percentage of skipping transcripts is low in cells and relatively higher in cfRNA. Since exon 2 skipping deletes the transmembrane domain, this BCMA protein may remain in the cytoplasm or perhaps is secreted as cell-free BCMA protein. The demonstration of relatively higher levels of BCMA∆Ex2 in cfRNA is likely reflecting higher turnover of cells and raises the possibility that cells with this isoform of BCMA are more aggressive than cells without the expression of this isoform. Further studies are needed to explore the clinical relevance of the expression of such abnormal BCMA protein on treatment with the various forms of anti-body-based therapy or CAR-T.
BCMA-directed CART therapy in patients with multiple myeloma and CNS involvement.
Authors: Gaballa Mahmoud R. , Castaneda Puglianini Omar Alexis , Cohen Adam D. , Vogl Dan T. , Chung Alfred , Ferreri Christopher J. , Voorhees Peter M. , Hansen Doris K. , Patel Krina K.
Published: June 2024

7519

Background: CART therapy represents a breakthrough in therapy for patients (ptns) with relapsed or refractory (R/R) multiple myeloma (MM). Pts with MM who have CNS involvement are commonly excluded from clinical trials and have limited therapeutic options. We evaluated the safety and efficacy of BCMA-directed CART therapies in ptns with MM and CNS involvement. Methods: 5 US academic medical centers contributed data to this retrospective analysis. 11 ptns with MM with CNS involvement received BCMA-directed CART (7 and 4 pts received ide-cel and cilta-cel, respectively). Results: Eight (72%) ptns were male, 3 (27%) had high-risk (HR) cytogenetics, and 10 (91%) had extramedullary disease (dz). Four (36%) ptns had brain/cranial nerve dz, 1 (9%) had spine dz, and 6 (55%) had both. CNS dz was evident on MRI in 100% of ptns and on CSF in 4 ptns (36%). Five ptns (45%) had ≤60 days between CNS diagnosis and CART therapy, 3 (27%) had >300 days from CNS dz with 2 requiring CNS-directed therapy (CNS-Tx) close to CART during bridging, and 3 (27%) were diagnosed soon after CART infusion. Six (55%) ptns received CNS-Tx as part of bridging; radiotherapy (RT, 2 ptns), RT + intrathecal (IT) chemotherapy (chemo) (2 ptns), IT chemo (1 ptn), and surgery + RT (1 ptn). Five (45%) ptns didn’t receive CNS-Tx as part of bridging for the following reasons; 3 were diagnosed soon post CART and received RT post-infusion, 1 had recent chemo, and 1 was treated for CNS dz 587 days prior to CART and didn’t require CNS-Tx during bridging. Seven ptns (64%) had treated CNS dz at the time of lymphodepleting chemo. Nine (82%) ptns had grade (G) 1/2 CRS and none had G ≥3CRS. Two ptns (18%) had G1 ICANS, 1 (9%) had G3 ICANS, and none had G4 ICANS. Two ptns experienced delayed neurotoxicity post ide-cel, 1 with delayed lethargy that was treated with steroids, and the other with progressive multifocal leukoencephalopathy that was treated with steroids plus pembrolizumab. None had delayed parkinsonian side effects. With a median follow-up of 104 days post-infusion, the best responses achieved were 45% CR/sCR, 18% VGPR, 9% PR, with an overall response (ORR) of 73%. Seven ptns were evaluable for CNS responses by day 90 with a 100% CNS response rate defined by improved imaging findings or clearance of CSF involvement. CNS recurrence occurred in 1 ptn (9%) by day 172 while 5 (45%) had continued systemic response at last assessment. Conclusions: This study suggests that BCMA directed CART therapy in ptns with MM and CNS involvement is safe and feasible. Of the evaluable ptns for CNS response, 100% showed CNS response by day 90. Larger studies with longer follow up are needed to confirm these findings. [Table: see text]
Evaluation of a novel method to guide belantamab mafodotin dosing in multiple myeloma based on a patient-reported questionnaire.
Authors: Terpos Evangelos , Gavriatopoulou Maria , Ntanasis-Stathopoulos Ioannis , Malandrakis Panagiotis , Fotiou Despina , Migkou Magdalini , Theodorakakou Foteini , Spiliopoulou Vasiliki , Syrigou Rodanthi , Eleutherakis Papaiakovou Evangelos , Gkolfinopoulos Stavros , Psarros Giorgos , Kastritis Efstathios , Dimopoulos Meletios Athanasios
Published: June 2024

7530

Background: Ocular adverse events (OAEs, best corrected visual acuity [BCVA] change from baseline and keratopathy) are common with belantamab mafodotin (belamaf; GSK2857916) and often necessitate an ophthalmic exam to guide dosing. Herein, we evaluate a novel approach for belamaf dose modifications in transplant ineligible patients (pts) with newly diagnosed MM, treated with an extended schedule of belamaf with lenalidomide and dexamethasone (Rd) in the BelaRd study. Methods: BelaRd (NCT04808037) is an ongoing, phase 1/2 study of 2 Parts. Part 1 established the recommended phase 2 dose (RP2D) of 1.9 mg/kg q8w, extended to q12w to account for OAEs. Part 2 assesses the safety/efficacy of RP2D in Groups A and B, of 15 pts each, and evaluates two sets of guidelines for OAE management. In Group A, dosing is determined by an ophthalmic exam performed by a certified ophthalmologist; in Group B it is determined by the pts’ responses in the Vision Related Anamnestic (VRA) tool and the presence of ≥Grade (Gr) 3 OAEs. VRA is a patient-reported questionnaire capturing ocular symptoms and their impact on activities of daily living (ADL). Herein, we present the OAEs and preliminary efficacy results after 205 ophthalmic and VRA assessments for all Part 2 pts (cut-off date 05/10/2023). Results: By the cut-off date, the median belamaf administrations and number of cycles reached were 3.0/3.0 and 8.0/7.0 for Groups A and B, respectively. The respective rates of Gr2 and ≥Gr3 BCVA change from baseline were 34.6%/24.2% and 6.4%/0.0%, while a meaningful BCVA decline (Snellen score <20/50) and ≥3 lines drop in the better-seeing eye was recorded in 11.0%/7.2% ophthalmological assessments; no ≥Gr3 keratopathy was observed. Among 110/94 VRA assessments, ocular symptoms and ADL impairment, manifesting for ≥50% of the time in the last 24 hours prior to belamaf administration (substantial time), were noted in 6.4%/10.6% and 3.6%/7.4%. Of note, VRA captured a “substantial time” response in 86% of assessments with ≥Gr3 OAEs. Finally, for the response-evaluable pts, at a median follow-up of 7.7 months, ORR was 93.3%/85.7% in Groups A and B (PR/VGPR/CR: 26.7%/53.3%/13.3%; 21.4%/64.3%/0.0%) and the median time to first response was ~ 1 month. Conclusions: The VRA tool was safe and effective in informing belamaf dose modifications. Future analyses will determine if VRA may effectively eliminate the need for an ophthalmic exam prior to belamaf dosing. Clinical trial information: NCT04808037 . [Table: see text]
Second primary B-ALL after exposure to lenalidomide for multiple myeloma: A US multicenter study.
Authors: Lakshman Arjun , Jensen Jeffrey Lee , Chakraborty Rajshekhar , Shaw Gene , Jevremovic Dragan , Shi Min , Cook James R , Monaghan Sara A , Abeykoon Jithma P. , Parrondo Ricardo , Bergsagel Peter Leif , Agha Mounzer E. , Rubinstein Sam , Coombs Catherine Callaghan , Ito Sawa , Shah Mithun Vinod , Advani Anjali S. , Baughn Linda , Kumar Shaji
Published: June 2024

7533

Background: Maintenance treatment (rx) with lenalidomide (R) improves overall survival (OS) in multiple myeloma (MM). We report a retrospective cohort of patients (pts) with second primary B-cell acute lymphoblastic leukemia (ALL) diagnosed after R-rx for MM. Methods: We included pts who were exposed to at least 1 yr of R for MM rx prior to ALL dx. After approval by institutional review board, data were collected by chart review at participating centers using Redcap. OS was the primary endpoint. We used BlueSky statistics v10.3.1 for analysis. Results: Analysis included 33 ALL pts diagnosed from 2014-2022 at 7 sites. 52% pts were female. Median follow up was 9.6 yrs (95%CI,7.6-11.8) from MM dx and 3.2 yrs (CI, 2.1-4.7) from ALL dx. Pt characteristics at MM dx are given in Table. Induction rx included: proteasome inhibitor (PI) +immunomodulatory drug (IMiD) (43%), PI+alkylator (24%), IMiD (18%) & others (15%). 50% pts received autologous stem cell transplantation (ASCT). Median OS from MM dx was 11.2 yrs (CI, 8.9-NR). Time from MM dx and initial R rx to ALL dx were 5.0 yrs (range, 2.4-18.5) and 4.4 yrs (2.2-10.6) respectively. Median duration of R exposure before ALL dx was 3.8 yrs (1.6-10.4). Table shows characteristics of pts at B-ALL dx and genetic classification based on karyotyping (n=30), ALL FISH (n=28), chromosomal microarray (n=5) and next-generation sequencing (n=5). 31 pts received ALL-directed rx while 1 pt was initially managed with close observation as the pt attained CR on stopping R ( Lakshman et al; ASH 2019 ). Rx was unknown in 1 pt. Initial rx included: hyper-CVAD+/- rituximab- 49%, pediatric inspired protocols-18%, reduced intensity rx for frail pts- 21% and others- 12%. Response to first line rx were: CR- 56%, CRi- 28%, induction failure- 16%. 32% pts attained measurable residual disease (MRD) negativity. 48% pts underwent SCT for ALL. 14 pts died during follow up. 3-yr OS from ALL-dx was 50% (CI, 33%-76%). 3 pts required rx for MM after ALL diagnosis (2 had allo-SCT for ALL before MM relapse). Conclusions: Most pts had standard risk MM and were exposed to R for several years prior to dx of B-ALL, characterized by high incidence of hypodiploid karyotype; IKZF1 loss and TP53 deletions/mutations were detected in a subset of pts.MRD-adapted timely discontinuation of R in standard risk MM may decrease risk of second primary ALL. [Table: see text]
Incidence of acute kidney injury in patients with relapsed and refractory multiple myeloma treated with teclistamab vs chimeric antigen receptor T-cell therapy.
Authors: Charkviani Mariam , Vaughan Lisa E , Sandahl Tyler B , Lin Yi , Leung Nelson , Herrmann Sandra M
Published: June 2024

7542

Background: Teclistamab, a novel bispecific monoclonal antibody targeting CD3 and BCMA, exhibits promising effects for patients with relapsed and refractory multiple myeloma (MM). However, rates of acute kidney injury (AKI) associated with this therapy remains inadequately characterized. Methods: This was a retrospective observational cohort study of patients with relapsed refractory MM who received teclistamab or Chimeric Antigen Receptor T-cell Therapy (CAR-T) therapy at Mayo Clinic between 12/1/2022-5/15/2023 and who were not in kidney failure at the time of treatment. The primary endpoint was incidence of AKI during follow-up; secondary endpoints included treatment and recovery from AKI. AKI was defined based on Kidney Disease Improving Global Outcomes criteria as an increase of serum creatinine levels > 1.5 times their baseline value after starting therapy. Cumulative incidences and Cox proportional hazard regression models were used to evaluate time to event data. Results: A total of 64 patients met inclusion criteria for the study (30 received CAR-T and 34 received teclistamab therapy). There were 14 AKI events occurring during follow-up (10 teclistamab [n = 6 stage 1, n = 3 stage 2 and n = 1 stage 3] and 4 CAR-T [n = 3 stage 1 and n = 1 stage 2]). Cumulative incidence estimates of AKI at 120 days after treatment were 32% (95% CI: 14%-47%) for teclistamab patients and 10% (95% CI: 0%-21%) for CAR-T patients. While patients receiving teclistamab were found to be at increased risk of an incident AKI event compared to patients receiving CAR-T therapy, results were not statistically significant (HR (95% CI): 3.38 (0.93-12.31), p = 0.065). Median time to development of AKI was 30 days (IQR 16, 73) in teclistamab and 59 days (IQR 9, 146) in CAR-T patients. Among the 10 patients in the teclistamab group with an AKI event, 4 (40%) had complete renal recovery and 4 (40%) had partial recovery, while among the 4 patients with CAR-T with an AKI event, 2 (50%) experienced complete renal recovery and 2 (50%) experienced partial recovery. Conclusions: Our study showed that almost one third of patients receiving teclistamab therapy for relapsed and refractory multiple myeloma experienced an incident AKI event during follow-up. This finding underscores the importance of monitoring for kidney function in these patients.
Population attributable fractions for risk factors for the progression of monoclonal gammopathy of undetermined significance to multiple myeloma in the Veteran population.
Authors: Wang Mei , Ji Mengmeng , Schoen Martin W. , Sanfilippo Kristen Marie , Thomas Theodore Seth , Chang Su-Hsin
Published: June 2024

7552

Background: Multiple myeloma (MM) is the most common type of plasma cell cancer in the U.S. MM is consistently proceeded by monoclonal gammopathy of undetermined significance (MGUS). Studies have identified several risk factors for the progression of MGUS to MM. However, the contribution of each of these risk factors has not been quantified. We computed the population attributable fractions (PAFs) for selected risk factors in the U.S. Veterans Health Administration (VHA) health system. Methods: Veterans diagnosed with MGUS from 1999-2021 were identified and confirmed via a published natural language processing (NLP) model. We included Black and White patients whose immunoglobulin (Ig) subtype was IgA, IgG, or light chain. Patients who progressed to MM ≤6 months after MGUS diagnosis were excluded. We fit a multivariable time-to-event model controlling for sex, race (Black, White), Ig subtype (IgA, IgG, light chain), agent orange (AO) exposure, as well as M-protein level (≤, >1.5 g/dL), Charlson Comorbidity Index (CCI), obesity status (underweight, normal weight, overweight, obese), and age, all at MGUS diagnosis. The outcome was progression of MGUS to MM, which was also confirmed by a published NLP model. PAF for a risk factor is the fraction of all MM cases in the veteran population that is attributable to this specific risk factor. It accounts for both the prevalence and relative risk of this factor in the population. We calculated PAF for black race, IgA, AO exposure, and overweight/obesity. Results: The analysis included 24,917 patients with MGUS. Among them, 7.8% (n=1,944) progressed to MM (follow-up median 5.6, IQR 3.3-8.8 years). In the veteran population with MGUS, 17.9% of all MM cases was attributable to overweight or obesity (PAF 17.9%, 95% confidence interval [CI] 11.0-24.3%); 7.6% was attributable to black race (PAF 7.6%, 95% CI 4.3-10.9%), 5.7% was attributable to IgA (PAF 5.7%, 95% CI 4.0-7.4%), and 2.4% was attributable to AO exposure (PAF 2.4%, 95% CI 1.0-3.9%). Conclusions: In the veteran population with MGUS, overweight/obesity, the only modifiable factor, is the top contributor to progression to MM cases. In veterans with MGUS, had the overweight or obese MGUS patients to be reversed to normal weight, an estimated 17.9% of the progression cases could have been avoided.Our findings highlight the importance of maintaining a normal weight for reducing the risk of progression of MGUS to MM. [Table: see text]
Real-world outcomes (RWO) with tandem transplantation in patients (pts) with newly diagnosed multiple myeloma (NDMM).
Authors: Parmar Harsh , Barcellos Anna , Biran Noa , Phull Pooja , Vesole David H. , Belli Andrew J. , Fernandes Laura L. , Hansen Eric , Zettler Christina , Wang Ching-Kun , Goran Stefanie , Anderson Courtney , Doucette Kimberley , Gunning Thomas S , Ip Andrew , Siegel David Samuel DiCapua
Published: June 2024

7564

Background: Stem cell transplant (SCT) followed by maintenance therapy (MT) is the standard of care for transplant eligible NDMM pts. Tandem transplantation has been found to have progression free (PFS) and overall survival (OS) benefit particularly for patients with high-risk cytogenetic abnormalities (HRCA). However, this modality remains under-utilized in clinical practice. We report RWO with tandem transplant (TT) in comparison with single SCT followed by MT (STM). Methods: We performed a multi-center, retrospective, observational study using the de-identified COTA real-world database derived from the EMRs of US centers. Pts with NDMM from 1/1/2012 to 1/1/23 were included in the study. Kaplan-Meier method was used to evaluate time to next treatment (TTNT), OS, follow-up time (reverse OS endpoint), and report log-rank test p-values. TTNT was defined in two ways: time from 1st SCT (2nd if TT) to the earliest of initiation of next line of therapy (LOT) or death (TTNT1) and the time from 2nd LOT post-SCT to the earliest of initiation of next LOT or death (TTNT2). A propensity score (PS) model was used to compare study cohorts, and hazard ratios (HRs) were estimated using the Cox proportional hazards method. HRCA were defined as pts with 17p(-), t(4;14), t(14;16), t(14;20) and 1q+. Results: 1117 pts met the study criteria. Median age at diagnosis was 60 yrs. 56.9% were male, 68.9% were White, and 32% had HRCA. 937 pts received STM and 180 pts received TT with median follow-up time of 68 months (mos) (95% CI: 65.4, 71.9) and 39 mos (95% CI: 31.9, 50.1), respectively. Median TTNT1 for TT vs STM was 52.7 vs 51 mos, (p=0.85), respectively. Median TTNT2 for TT vs STM was 33.9 vs 11.8 mos, (p<0.001). respectively. Median OS for TT vs STM was not reached (NR) vs 108.1 mos, (p<0.001), respectively. In the PS model, the TT group had significantly lower hazard of TTNT2 and OS events (HRs 0.49 and 0.47, p<0.001 and p=0.01, respectively) as compared to STM. Conclusions: Our study demonstrates significant improvement in unadjusted TTNT2 and OS RWO for TT pts, despite higher incidence of HRCA compared to STM pts. PS analysis demonstrated a similar effect with decreased HRs for TT. OS is an extremely difficult primary outcome to achieve in MM RCTs where survival may have to be collected for decades. Thus, our large study of RWO with long-term follow-up is valuable. [Table: see text]
Automated myeloma cell selection using machine learning and artificial intelligence.
Authors: Louis Sherif , Knecht Hans , Mai Sabine
Published: June 2024

7565

Background: Precision of sampling is critical to achieve accurate results relevant to diagnostics and prognostics. Sampling errors may compromise the sensitivity and specificity of otherwise credible diagnostics technologies. Our 3- dimensional (3D) telomeres profiling methodology is conducted on individual target cells selected from the patient sample processed using 3D immuno-FISH. In our traditional workflow target cells are manually selected by highly trained personnel based on morphological characteristics and/ or immunophenotypic characteristics, namely cells positive for CD138 and CD56. However, the variability among trained operators required rounds of verification by a second and third operator and an approval by a Hematopathologist or the Lab Director to confirm the selected cells in some cases. Therefore, automated detection of myeloma cells is of paramount importance. Methods: In this study we employed machine learning and artificial intelligence (AI) tools to develop an automated algorithm capable of streamlining target cell (i.e. myeloma) selection and minimize or eliminate operator introduced variability. Training libraries were built using positive and negative cells. Over 5000 cells were used in the algorithm training process. We employed iterative rounds of validation and refinement to achieve a high precision automated tool. AI then identified myeloma cells in an automated fashion and the results of AI identification were confirmed by a Hematopathologist. Results: We report the results of a comparative analysis done on 20 myeloma patients at different stages of the disease including MGUS, smouldering myeloma and active myeloma. Also, the sample type included bone marrow smears, purified mono-nucleated plasma cells and bone marrow biopsies. 50 verified manually selected target cells and 50 target cells selected by the automated cell selection tool, approved by a skilled operator, from the same sample of each patient were analyzed using the TeloView platform. The TeloView platform quantifies 6 telomeric molecular and structural parameters. We conducted statistical analysis to calculate Coefficient of Variation (CV) between the results of each patient. We set the acceptable variability to < 15%. We achieved CVs of less than 10% among all patients included in the analysis. Conclusions: The automated cell selection tool streamlined this critical sampling process in our workflow minimizing operator-introduced variability, reducing the processing time to a fraction of the time required for manual cell selection and verification which enables high throughput for the 3D telomeres profiling while maintaining precision.
1p and 1q: Partners in crime in multiple myeloma.
Authors: Devarakonda Srinivas S. , Vaishnav Arti , Zhao Qiuhong , Bumma Naresh , Cottini Francesca , Sharma Nidhi , Umyarova Elvira , Rosko Ashley Elizabeth , Benson Don M. , Khan Abdullah Mohammad
Published: June 2024

7571

Background: Cytogenetic abnormalities in multiple myeloma (MM) highly influence the disease course, response to treatment and survival. Trisomies and immunoglobulin H chain translocations are primary CA while del(17p), gain(1q), del(1p) among others are secondary CA. Gain (3 copies) and amplification (>3 copies) 1q have been recognized as adverse prognostic markers and incorporated into the second revision of the International Staging System (R2-ISS). However, the role of del(1p) is less well defined, especially in the era of novel therapies. We aimed to analyze the outcomes of newly diagnosed MM (NDMM) patients with chromosome 1 abnormalities, mainly del 1p, treated with autologous stem cell transplant (ASCT) consolidation at our institution. Methods: We conducted a retrospective study of all NDMM patients who were treated with ASCT from 1/1/2015-2/13/2019 (n=511). High-risk cytogenetics (HRC) were defined by the presence of del(17p), t(4;14), or t(14;16) similar to R-ISS; standard-risk cytogenetics (SRC) were defined as the absence of HRC. Modified HR cytogenetics (mHRC) included gain/amp 1q and/or t(14;20) in addition to HRC, while ultra high-risk (uHRC) included 2 or more mHRC CA. Results: Of 511 pts transplanted, 453 had cytogenetic data at the time of diagnosis. SRC were seen in 353 pts (77.9%), while 100 (22.1%) had HRC, 156 (34.4%) had mHRC, and 43 (9.5%) had uHRC. Thirty-two (7.1%) pts had del(1p) while 105 (23.2%) had gain 1q and 30 (6.6%) had amplification 1q. As expected, compared to SRC pts, pts with HRC, mHRC and uHRC had higher risk of relapse or death. Patients with gain and amp 1q had inferior outcomes in terms of progression-free survival (PFS) (HR 1.35; 95% CI 1.06-1.73, p=0.016), time to next treatment (TTNT) (HR 1.84; 95% CI 1.40-2.42, p<0.001) and overall survival (OS) (HR 1.47; 95% CI 1.06-2.02, p=0.02) compared to those without, consistent with published literature. The median PFS, TTNT and OS from ASCT in pts with gain/amp 1q were 3.17 years (y), 3.95y and 7.13y, respectively, compared to 4.01y, 7.60y and 8.21y in pts without gain/amp 1q. Pts with del(1p) had inferior PFS (median 2.43y versus 3.98y; HR 1.75; 95% CI 1.16-2.64, p=0.008), TTNT (median 2.72y versus 6.17y; HR 1.96; 95% CI 1.22-3.14, p=0.005) and OS (median 4.11y versus 8.38y; HR 2.19; 95% CI 1.34-3.58, p=0.002) from the time of ASCT compared to those without del(1p). Conclusions: In our study of NDMM patients that underwent AHCT, del(1p) at diagnosis was an independent predictor of shorter PFS, TTNT and OS. Despite induction therapy involving novel drugs and ASCT consolidation, patients with del(1p) at diagnosis continue to have inferior outcomes. Larger analyses are needed to validate the prognostic value of del(1p) and investigate its role in predicting outcomes in MM.
Retrospective analysis of change in frequency of STK11 mutation in lung adenocarcinomas over a 10-year period.
Authors: Parekh Deevyashali , Basnet Alina , Pavlick Dean , Ross Jeffrey S. , Graziano Stephen L.
Published: June 2024

8032

Background: Previous studies have linked the presence of inactivating mutations in the tumor suppressor gene STK11 with reduced efficacy of immune checkpoint inhibitor (ICI) treatments in lung adenocarcinoma (LA). We queried whether there has been a change in the STK11 mutation frequency over the last 10-year period that could potentially reflect the emergence of additional acquired resistance mutations. Methods: Over a 10-year period from 2013 through 2022, 109,763 clinically advanced LA underwent hybrid capture based comprehensive genomic profiling (CGP) to assess all classes of genomic alterations (GA) at a single reference laboratory (Foundation Medicine). MSI-high status and tumor mutational burden (TMB) were determined from the sequencing data. PD-L1 status was measured by immunohistochemistry (IHC) using the Dako 22C3 kit with TPS scoring. Statistical comparisons utilized the 2-tailed Chi Square method with the Yates’ correction. Results: The frequency of STK11 inactivating GA in all cases of LA significantly increased during the study period from 2013 to 2022 (16.1% vs 20.1%; p=0.0005). This increase appeared to be predominantly in KRAS wild type LA (10.1% vs 15.5%; p<0.0001). The STK11 GA frequency slightly declined in the KRAS mutated LA over the 10-year period (29.9% vs o 27.0%, P=0.25). During the same time period, the KEAP1 GA frequency increased from 12.6% to 14.9% (p= 0.076) and the frequency of combined STK11 and KEAP1 GA increased from 4.8% to 8.0% (p=.0006). The frequencies of MSI-high status, TMB and PD-L1 expression did not significantly change over the observation period. Conclusions: The continuously increasing approved indications for ICI-based treatments for both early stage and clinically advanced LA appears to be accompanied by a significant increase in the frequency of inactivating STK11 GA predominantly in the KRAS mutation negative LA population. This inactivation is associated with an attenuated response rate and progression-free survival in this population. Given the development of novel therapies focused on potential restoration of STK11 function by HDAC/CoREST inhibition, further study of the STK11 GA distribution in LA appears warranted. [Table: see text]
Differentially expressed microRNAs in prediagnostic serum linked to lung cancer up to eight years before diagnosis in prospective, population-based cohorts: A HUNT study.
Authors: Nguyen Olav Toai Duc , Fotopoulos Yannis , Nøst Therese Haugdahl , Markaki Maria , Lagani Vincenzo , Sætrom Pål , Tsamardinos Ioannis , Røe Oluf Dimitri D.
Published: June 2024

8041

Background: With lung cancer incidence and mortality on the rise, blood biomarkers are increasingly in demand for early detection. The aim of this study is to discover and validate novel biomarkers based on next-generation sequencing performed on blood samples from non-cancer, ever-smokers up to eight years prior to diagnosis. Methods: Initial consideration was given to serum samples from the population-based prospective HUNT2 and HUNT3 cohorts, age > 18 (n = 98,737). Inclusion criteria for cases were ever-smokers, no prior cancer at study entry, and 0–8 years between blood sampling and lung cancer diagnosis in the discovery and 0-4 years in the validation cohort. Among future cases, equal numbers of adenocarcinoma, squamous cell carcinoma and small-cell lung carcinoma were included. Every subsequent case of lung cancer had a matched control, ratio 1:1. The controls were matched for sex, age at study entry, pack-years, smoking cessation duration, comparable HUNT Lung Cancer Model risk score and no cancer diagnosis until the end of the study. The total number of serum samples included in the discovery and validation dataset were 240 (from HUNT2) and 72 (from HUNT3), respectively. The samples were analyzed by genome-wide small RNA seq (Illumina). Results: When we contrasted all cases against all controls, nine differentially expressed microRNAs with AUC > 0.60 (FDR < 0.25) and total raw count of > 0.5 appeared in common in the discovery and validation datasets. Among these, three microRNAs were associated with non-small cell metastatic with mean AUC of 0.65 and 0.76 in the discovery and validation datasets, respectively. Furthermore, the signature of these three microRNAs in combination reached an AUC of 0.75 (discovery) and 0.90 (validation). Conclusions: Up to eight years before diagnosis, a small number of substantially differentially expressed microRNAs were found in serum. These intriguing microRNAs can potentially function as early diagnostic indicators for lung cancer, either alone or in combination. Further investigation and validation of these results in a larger prospective serum dataset are required.