Faculty Bibliography

BACKGROUND:Lenalidomide maintenance has long been a preferred treatment after autologous haematopoietic stem-cell transplantation (HSCT) in patients with multiple myeloma. Multidrug treatments are emerging as an alternative to lenalidomide alone. We aimed to compare carfilzomib-lenalidomide-dexamethasone with lenalidomide alone in patients with multiple myeloma after autologous HSCT. METHODS:on days 1, 2, 15, and 16 from cycle 5 to 36; lenalidomide 25 mg administered orally on days 1-21; and dexamethasone 20 mg administered orally on days 1, 8, 15, and 22) or lenalidomide (10 mg administered orally for the first three cycles and then at the best tolerated dose [≤15 mg for 28 days in 28-day cycles]). Randomisation was stratified by response to previous treatment at trial entry (less than very good partial response vs very good partial response or better), cytogenetic risk factors (presence vs absence of any of del[13], t[4;14][p16;q32], t[14;16][q32;q23], del[17][p13.1], or hypodiploidy), and site location (USA vs Poland). Patients in the carfilzomib-lenalidomide-dexamethasone group with standard cytogenetic risk were switched to lenalidomide maintenance after cycle 8 if no measurable residual disease (MRD) was detected after cycle 6. The primary endpoint was progression-free survival in all randomly assigned patients. The safety analysis population included all randomly assigned patients who received at least one dose of the assigned treatment. This study was registered with ClinicalTrials.gov (NCT02659293) and EudraCT (2015-002380-42) and is completed. FINDINGS/RESULTS:Between June 10, 2016, and Oct 21, 2020, 196 patients consented and were screened for eligibility, 180 of whom were enrolled and randomly assigned to carfilzomib-lenalidomide-dexamethasone (n=92) or lenalidomide (n=88). 85 (47%) patients were female and 95 (53%) were male; 167 (93%) were White. At a median follow-up of 69 months (IQR 57-77), 4-year progression-free survival was 67·5% (95% CI 56·2-76·4) in the carfilzomib-lenalidomide-dexamethasone group and 38·0% (27·6-48·2) in the lenalidomide group (p<0·0001; median progression-free survival 72·8 months [58·4-not estimable] vs 37·3 months [30·6-44·7]; hazard ratio 0·46 [95% CI 0·30-0·70]; log-rank p=0·0002). The most common grade 3-4 adverse events were neutropenia (44 [48%] of 91 patients in the carfilzomib-lenalidomide-dexamethasone group vs 51 [59%] of 87 in the lenalidomide group) and thrombocytopenia (12 [13%] vs five [6%]). Serious adverse events occurred in 27 (30%) patients in the carfilzomib-lenalidomide-dexamethasone group and 20 (23%) in the lenalidomide group. Two deaths in the carfilzomib-lenalidomide-dexamethasone group due to lung infections and two deaths in the lenalidomide group due to COVID-19 and heart failure were considered possibly related to treatment by the investigators. INTERPRETATION/CONCLUSIONS:The enhanced efficacy of carfilzomib-lenalidomide-dexamethasone treatment following autologous HSCT in patients with newly diagnosed multiple myeloma, assessed within a framework of de-escalation based on MRD status and individual risk, supports strategies for maintenance therapy intensification in this setting. FUNDING/BACKGROUND:Amgen and Celgene (Bristol Myers Squibb).

Consumption of a western diet and high body mass index (BMI) are risk factors for progression from pre-malignant phenotypes to multiple myeloma, a hematologic cancer. In the NUTRIVENTION trial (NCT04920084), we administered a high-fiber, plant-based diet (meals for 12 weeks, coaching for 24 weeks) to 23 participants with myeloma precursor states and elevated BMI. The intervention was feasible, improved quality of life and modifiable risk factors: metabolic (BMI, insulin resistance), microbiome (diversity, composition), and immune (inflammation, monocyte subsets). Disease-progression trajectory improved (n=2) or was stable. Findings were translated to Vk*MYC mice modeling the myeloma-precursor state, in which a high-fiber diet delayed disease progression through improved metabolism and microbiome composition leading to increased short-chain fatty acid production that reinvigorated anti-tumor immunity and inhibited tumor growth. These effects from fiber consumption were independent of calorie restriction and weight loss. A high-fiber diet is a low-risk intervention that may delay progression to myeloma.

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.

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.

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.

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.

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.

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.