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A multiomic analysis of Waldenström macroglobulinemia defines distinct disease subtypes

Gagler, Dylan C; Ghamlouch, Hussein; Zhang, Di; Blaney, Patrick; Tenenbaum, Avital; Langton, James Blake; Armand, Marine; Eeckhoutte, Alexandre; Joudat, Amina; Degaud, Michaƫl; Esposito, Michela; Varma, Gaurav; Wang, Yubao; Lee, Sanghoon; Liu, Sanxiong; Lahoud, Oscar B; Kaminetzky, David; Braunstein, Marc J; Williams, Louis; Nguyen-Khac, Florence; Walker, Brian A; Roos-Weil, Damien; Davies, Faith E; Bernard, Olivier A; Morgan, Gareth J
We carried out a single-cell (sc) multiomic analysis on a series of MYD88 mutated Waldenström macroglobulinemia (WM) cases and identified two distinct subtypes of disease, memory B-cell-like (MBC-like) and plasma cell-like (PC-like), based on their expression of key lineage defining genes. Biologically, the subtypes are characterized by their variable capacity to differentiate fully towards a plasma cell (PC) and exhibit unique transcriptomic, chromatin accessibility, and genomic profiles. The MBC-like subtype is unable to differentiate beyond the memory B-cell (MBC) stage, upregulates key MBC genes, and is characterized by upregulated BCR and AKT/mTOR signaling. In contrast, the PC-like subtype can partially differentiate towards a PC, upregulates key PC genes, has enhanced NF-kB signaling, and has an upregulated unfolded protein response. Pseudotime trajectory analysis of combined scRNA-sequencing and scATAC-sequencing supports the variable differentiation capacity of each subtype and implicate key transcription factors SPI1, SPIB, BCL11A, and XBP1 in these features. The existence and generalizability of the two disease subtypes were validated further using hierarchical clustering of bulk RNA-seq data from a secondary set of cases. The biological significance of the subtypes was further established using whole genome sequencing, where it was shown that CXCR4, NIK, and ARID1A mutations occur predominantly in the MBC-like subtype and 6q deletions in the PC-like subtype. We conclude that the variable differentiation blockade seen in WM manifests itself clinically as two disease subtypes with distinct epigenetic, mutational, transcriptional, and clinical features with potential implications for WM treatment strategies.
PMID: 40332467
ISSN: 1528-0020
CID: 5839202

A Shared Care Model between community and transplant centers facilitates access to allogeneic and autologous transplantation

Fein, Joshua A; McAuliffe, Agnes; Fischer, Kimberly; Brady, Owen; Devlin, Sean M; Willumsen, Silvia; Ozcan, Gonca; Montanaro, Pat; Pristyazhnyuk, Yelena; DiGiuseppe, Joseph; Lahoud, Oscar B; Perales, Miguel-Angel; Pfister, David G; Giralt, Sergio; Dailey, Mark; Yu, Peter Paul; Sauter, Craig Steven
Access to allogeneic and autologous hematopoietic stem cell transplantation (SCT) remains inadequate despite its curative potential across hematologic malignancies. In 2015, Hartford HealthCare (HHC) and the Memorial Sloan Kettering Cancer Center (MSK) established the Shared Care Model (SCM) with a primary aim of enhancing SCT access for HHC patients. The SCM comprises several components: an SCT-dedicated nurse-navigator, a health-information exchange for record sharing, telemedicine, and ongoing training of HHC clinicians in transplant patient selection and management. We evaluated the SCM's impact on SCT access across 126 patients with acute leukemia, myelodysplastic syndrome, and multiple myeloma from 2016-2020. The SCM facilitated 34 referrals. Socio-economic status of HHC referrals by Area Deprivation Index was significantly inferior (38 vs. 14, p < 0.001) when compared to 3,108 non-SCM referrals to MSK during the same period. Allogeneic recipients spent 68-247 days away from home, and autologous recipients 15-48, both requiring few subsequent visits to MSK.
PMID: 39641218
ISSN: 1029-2403
CID: 5818442

Evaluating serum free light chain ratio as a biomarker in multiple myeloma

Akhlaghi, Theresia; Maclachlan, Kylee; Korde, Neha; Mailankody, Sham; Lesokhin, Alexander; Hassoun, Hani; Lu, Sydney X; Patel, Dhwani; Shah, Urvi; Tan, Carlyn; Derkach, Andriy; Lahoud, Oscar; Landau, Heather J; Shah, Gunjan L; Scordo, Michael; Chung, David J; Giralt, Sergio A; Usmani, Saad Z; Landgren, Ola; Hultcrantz, Malin
PMCID:11788616
PMID: 39363855
ISSN: 1592-8721
CID: 5818472

Artificial intelligence enabled interpretation of ECG images to predict hematopoietic cell transplantation toxicity

Shaffer, Brian C; Brown, Samantha; Chinapen, Stephanie; Mangold, Kathryn E; Lahoud, Oscar; Lopez-Jimenez, Francisco; Schaffer, Wendy; Liu, Jennifer; Giralt, Sergio; Devlin, Sean; Shah, Gunjan; Scordo, Michael; Papadopoulos, Esperanza; Landau, Heather; Usmani, Saad; Perales, Miguel-Angel; Friedman, Paul A; Gersh, Bernard J; Attia, Itzhak Zachi; Noseworthy, Peter A; Kosmidou, Ioanna
Artificial intelligence (AI)-enabled interpretation of electrocardiogram (ECG) images (AI-ECGs) can identify patterns predictive of future adverse cardiac events. We hypothesized that such an approach would provide prognostic information for the risk of cardiac complications and mortality in patients undergoing hematopoietic cell transplantation (HCT). We retrospectively subjected ECGs obtained before HCT to an externally trained, deep-learning model designed to predict the risk of atrial fibrillation (AF). Included were 1377 patients (849 autologous [auto] HCT and 528 allogeneic [allo] HCT recipients). The median follow-up was 2.9 years. The 3-year cumulative incidence of AF was 9% (95% confidence interval [CI], 7-12) in patients who underwent auto HCT and 13% (10%-16%) in patients who underwent allo HCT. In the entire cohort, pre-HCT AI-ECG estimate of AF risk correlated highly with the development of clinical AF (hazard ratio [HR], 7.37; 95% CI, 3.53-15.4; P < .001), inferior survival (HR, 2.4; 95% CI, 1.3-4.5; P = .004), and greater risk of nonrelapse mortality (NRM; HR, 95% CI, 3.36; 1.39-8.13; P = .007), without increased risk of relapse. Association with mortality was only noted in allo HCT recipients, where the risk of NRM was greater. The use of cyclophosphamide after transplantation resulted in greater 90-day incidence of AF (13% vs 5%; P = .01) compared to calcineurin inhibitor-based graft-versus-host disease prophylaxis, corresponding to temporal changes in AI-ECG AF prediction after HCT. In summary, AI-ECG can inform risk of posttransplant cardiac outcomes and survival in HCT patients and represents a novel strategy for personalized risk assessment.
PMCID:11550362
PMID: 39158065
ISSN: 2473-9537
CID: 5818452

Colesevelam for lenalidomide associated diarrhea in patients with multiple myeloma [Letter]

Hultcrantz, Malin; Hassoun, Hani; Korde, Neha; MacLachlan, Kylee; Mailankody, Sham; Patel, Dhwani; Shah, Urvi A; Tan, Carlyn Rose; Chung, David J; Lahoud, Oscar B; Landau, Heather J; Scordo, Michael; Shah, Gunjan L; Giralt, Sergio A; Pianko, Matthew J; Burge, Miranda; Barnett, Kelly; Salcedo, Meghan; Caple, Julia; Tran, Linh; Blaslov, Jenna; Shekarkhand, Tala; Hamid, Selena; Nemirovsky, David; Derkach, Andriy; Arisa, Oluwatobi; Peer, Cody J; Figg, William D; Usmani, Saad Z; Landgren, Ola; Lesokhin, Alexander M
PMID: 39300066
ISSN: 2044-5385
CID: 5818462

Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma

Firestone, Ross S; Socci, Nicholas D; Shekarkhand, Tala; Zhu, Menglei; Ge Qin, Wei; Hultcrantz, Malin L; Mailankody, Sham; Tan, Carlyn Rose; Korde, Neha; Lesokhin, Alexander M; Hassoun, Hani; Shah, Urvi A; Maclachlan, Kylee H; Rajeeve, Sridevi; Landau, Heather J; Scordo, Michael; Shah, Gunjan L; Lahoud, Oscar B; Giralt, Sergio A; Murata, Kazunori; Usmani, Saad Z; Chung, David J
B-cell maturation antigen (BCMA)-targeting therapeutics have dramatically improved outcomes in relapsed/refractory multiple myeloma (RRMM). However, whether the mechanisms of resistance between these therapies are shared and how the identification of such mechanisms before therapy initiation could refine clinical decision-making remains undefined. We analyzed outcomes for 72 RRMM patients treated with teclistamab, a CD3 x BCMA bispecific antibody (BsAb), 42% (30/72) of whom had prior BCMA-directed therapy exposure. Malignant plasma cell BCMA expression was present in all BCMA therapy-naïve patients. Prior therapy-mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and one of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from one patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA-directed treatments, underscoring the importance of verifying the presence of a target antigen.
PMID: 38728378
ISSN: 1528-0020
CID: 5673312

Unscheduled health care interactions in patients with multiple myeloma receiving T-cell redirection therapies

Howard, Anna J; Concepcion, Isabel; Wang, Alice X; Hamadeh, Issam S; Hultcrantz, Malin; Mailankody, Sham; Tan, Carlyn; Korde, Neha; Lesokhin, Alexander M; Hassoun, Hani; Shah, Urvi A; Maclachlan, Kylee H; Rajeeve, Sridevi; Landau, Heather J; Scordo, Michael; Shah, Gunjan L; Lahoud, Oscar B; Chung, David J; Giralt, Sergio; Usmani, Saad Z; Firestone, Ross S
Outcomes for patients with relapsed/refractory multiple myeloma (R/RMM) have dramatically improved after the development and now growing utilization of B-cell maturation antigen-targeted chimeric antigen receptor (CAR) T-cell therapy and bispecific antibody (BsAb) therapy. However, health care utilization as a quality-of-life metric in these growing populations has not been thoroughly evaluated. We performed a retrospective cohort study evaluating the frequency and cause of unscheduled health care interactions (UHIs) among patients with R/RMM responding to B-cell maturation antigen-targeted BsAb and CAR T-cell therapies (N = 46). This included the analysis of remote UHIs including calls to physicians' offices and messages sent through an online patient portal. Our results showed that nearly all patients with R/RMM (89%) receiving these therapies required a UHI during the first 125 days of treatment, with a mean of 3.7 UHIs per patient. Patients with R/RMM responding to BsAbs were significantly more likely to remotely contact their physicians' offices (1.8-fold increase; P = .038) or visit an urgent care center (more than threefold increase; P = .012) than patients with R/RMM responding to CAR T-cell therapies. This was largely due to increased reports of mild upper respiratory tract infections in BsAb patients. Our results underscore the need to develop preemptive management strategies for commonly reported symptoms that patients with R/RMM experience while receiving CAR T-cell or BsAb therapies. This preemptive management may significantly reduce unnecessary health care utilization in this vulnerable patient population.
PMID: 38621239
ISSN: 2473-9537
CID: 5673302

Patterns of CRS with Teclistamab in Relapsed/Refractory Multiple Myeloma patients with Prior T-Cell Redirection Therapy

Hamadeh, Issam S; Shekarkhand, Tala; Rueda, Colin Joseph; Firestone, Ross S; Wang, Alice X; Korde, Neha; Hultcrantz, Malin L; Lesokhin, Alexander M; Mailankody, Sham; Hassoun, Hani; Shah, Urvi A; Maclachlan, Kylee H; Rajeeve, Sridevi; Patel, Dhwani; Shah, Gunjan L; Scordo, Michael; Lahoud, Oscar B; Chung, David J; Landau, Heather J; Giralt, Sergio A; Usmani, Saad Z; Tan, Carlyn Rose
Teclistamab (Tec) is a first-in-class BCMA X CD3 bispecific T-cell engager antibody approved for treating multiple myeloma progressing after at least 4 lines of therapy. The objective of this study was to evaluate the rate of cytokine release syndrome (CRS) in patients who were treated with commercial Tec and had prior exposure to other T-cell redirection therapies. A retrospective chart review was performed to identify patients who completed the Tec step-up dosing phase between November 2022 and November 2023. Patients were divided into 2 cohorts based on prior exposure to T-cell redirection therapy (cohort 1: T-cell redirection therapy experienced; cohort 2: T-cell redirection therapy naïve). The primary objective was to compare the differences in the rates of CRS between the two cohorts. Univariate and multivariate logistic regression analyses were performed to assess the association between CRS rates with Tec and prior treatment with T-cell redirection therapy. A total of 72 patients were included in the analysis (27 in cohort 1 and 45 in cohort 2). The CRS rates were significantly lower in cohort 1 (37%, n=10) compared to cohort 2 (80%, n=36; p=0.0004). Based on multivariate logistic regression analysis, patients without prior exposure to T-cell redirection therapy (cohort 2) had about a 4-fold increase in the incidence of CRS (95% CI: 1.40-14.90, p=0.0002) with Tec. In our study, prior exposure to T-cell redirection therapy reduced the risk of CRS with Tec during the step-up dosing phase. This observation will allow for the optimization of CRS prophylactic strategies for Tec.
PMID: 38598713
ISSN: 2473-9537
CID: 5647132

Colesevelam for Lenalidomide Associated Diarrhea in Patients with Multiple Myeloma

Hultcrantz, Malin; Hassoun, Hani; Korde, Neha; Maclachlan, Kylee; Mailankody, Sham; Patel, Dhwani; Shah, Urvi; Tan, Carlyn Rose; Chung, David J; Lahoud, Oscar; Landau, Heather; Scordo, Michael; Shah, Gunjan L; Giralt, Sergio; Pianko, Matthew J; Burge, Miranda; Barnett, Kelly; Salcedo, Meghan; Caple, Julia; Tran, Linh; Blaslov, Jenna; Shekarkhand, Tala; Hamid, Selena; Nemikovski, David; Derkach, Andriy; Arisa, Oluwatobi; Peer, Cody J; Figg, William D; Usmani, Saad Z; Landgren, Ola; Lesokhin, Alexander M
Lenalidomide maintenance is associated with a significantly improved progression-free in patients with newly diagnosed multiple myeloma. Maintenance with lenalidomide is generally well tolerated; however, lenalidomide associated diarrhea is a common side effect and bile acid malabsorption has been suggested as an underlying mechanism. We conducted a single arm phase 2 trial of colesevelam, a bile acid binder, for lenalidomide-associated diarrhea in multiple myeloma. Patients were treated with colesevelam daily starting at 1250 mg (2 tablets 625 mg) for 12 weeks. The trial included 25 patients, 1 patient with grade 3 diarrhea, 14 with grade 2, and 10 with grade 1 diarrhea. All patients were on treatment with single agent lenalidomide maintenance and no patient progressed during the trial. Colesevelam treatment was highly effective for treatment of lenalidomide-associated diarrhea; 22 (88%) of the 25 patients responded where 17 patients (68%) had complete resolution of diarrhea, and 5 patients (20%) had improvement by 1 grade of diarrhea. The responses to colesevelam were seen within the first two weeks of treatment. These findings support the conclusion that lenalidomide-associated diarrhea is driven by bile acid malabsorption. Five patients reported mild gastrointestinal side effects including constipation. Importantly, the pharmacokinetics of lenalidomide were not affected by concomitant colesevelam treatment. The stool microbiome composition was not significantly different before and after colesevelam treatment. Patients reported improved diarrhea, fewer gastrointestinal symptoms, and less interference with their daily life after starting colesevelam. In summary, colesevelam was safe and highly effective for treatment of lenalidomide-associated diarrhea in multiple myeloma and does not reduce the clinical effect of lenalidomide.
PMCID:11177961
PMID: 38883739
CID: 5673342

BEAM versus pharmacokinetics-directed BuCyVP16 conditioning for patients with peripheral T-cell lymphoma undergoing high-dose therapy with autologous hematopoietic cell transplantation [Letter]

Stuver, Robert; Mian, Agrima; Brown, Samantha; Devlin, Sean; Caimi, Paolo F; Chinapen, Stephanie; Dahi, Parastoo; Dean, Robert; Epstein-Peterson, Zachary D; Hill, Brian; Horwitz, Steven M; Lahoud, Oscar; Lin, Richard; Moskowitz, Alison J; Sauter, Craig; Shah, Gunjan; Winter, Alison; Jagadeesh, Deepa; Scordo, Michael
PMID: 38526002
ISSN: 1096-8652
CID: 5647122