ABSTRACT:Although obesity is an established modifiable risk factor for multiple myeloma (MM), the influence of obesity on survival among Black patients, among whom obesity and MM are more common, is less clear. We evaluated the association of body mass index (BMI) with progression free survival and overall survival among 834 histologically confirmed patients with newly diagnosed MM (NDMM) enrolled in the Integrative Molecular And Genetic Epidemiology study between 2009 and 2020. We estimated the association of BMI with the risk for progressed disease and all-cause and MM-specific mortality using hazard ratios (HR) and corresponding 95% confidence intervals (CI), calculated from multivariable Cox proportional hazard models adjusted for prognostic factors. When compared with NDMM patients with a normal BMI at diagnosis (18.5-24.9 kg/m2) positive associations with all-cause mortality were observed at the extremes with a 52% and 147% increased risk for death in patients with underweight (BMI, <18.5 kg/m2, HR, 1.52; 95% CI 0.48-4.84) and those with obesity (BMI, ≥30.0 kg/m2, HR, 2.47; 95% CI, 1.26-4.85), respectively. Patients with severe obesity (BMI, ≥35kg/m2) had the highest risk when compared with those with a normal BMI (HR, 3.14; 95% CI, 1.50-6.55), particularly among White (HR, 3.22; 95% CI, 1.30-7.94) and female (HR, 4.17; 95% CI, 1.20-14.47) patients with NDMM; however, the differences by race and sex were not statistically significant (Pinteraction ≥.60). Severe obesity was also associated with an 83% elevated risk for progressed disease among patients with NDMM (HR, 1.83; 95% CI, 1.04-3.24). These findings were similar for MM-specific mortality and highlight weight management as a potential strategy to improve the prognosis of all patients with NDMM.

Studies have reported conflicting findings regarding the contribution of germline variants or somatic genomic drivers to racial disparities in multiple myeloma. To comprehensively investigate somatic drivers in relation to inherited genetics in multiple myeloma, we combined newly sequenced whole-genome sequencing data with publicly available datasets (total n = 1,286). Overall, we did not identify germline or somatic genomic differences that explain the different risk of developing multiple myeloma between patients with genetic similarity to African (AFR) or European (EUR) reference populations. A difference in the detectability and timing of APOBEC-associated and germinal center mutational activity was observed. Integrating epidemiologic data and mutational signature-based temporal estimates, we challenge the assumption that individuals in the AFR group develop multiple myeloma at a younger age. Finally, we demonstrate that, with equal access to efficacious therapies, patients in the AFR and EUR groups have equivalent clinical outcomes. SIGNIFICANCE:Multiple myeloma is reported to occur at higher rates in individuals who self-identify as non-Hispanic Black. In this large dataset, genomic drivers occur at the same rate among ancestry groups, except for APOBEC mutagenesis. With equivalent therapy, clinical outcomes did not differ for patients grouped by genetic ancestry similarity.

The H3K36me2 methyltransferase NSD2 is deleted in Wolf-Hirschhorn syndrome and aberrantly expressed in 10-15% of multiple myeloma (MM) due to a t(4;14) translocation. Although NSD2 is thought to be a primary driver in MM, the exact molecular mechanisms by which it regulates transcription remain unclear. We applied the dTAG system to acutely degrade NSD2 and used this, in combination with time-resolved SLAM-seq, to identify 307 transcriptional targets of NSD2. Reconstitution with either wild-type NSD2 or a catalytically inactive mutant (NSD2Y1179A) showed that NSD2's transcriptional effects are almost exclusively dependent on its SET domain activity. Mechanistically, H3K36me2 deposition by NSD2 antagonizes H3K27me3 levels, and treatment with two distinct PRC2 inhibitors demonstrated that approximately half of NSD2 target genes are regulated in an H3K27me3-dependent manner. CUT&Tag analysis showed that upon NSD2 depletion there was an increase in H3K27me3 that occurred at genome-wide intergenic regions, rather than at the promoters or gene bodies of NSD2 target genes. These data suggest that NSD2, via H3K36me2, antagonizes H3K27me3 deposition likely at distal regulatory elements including enhancers, creating a chromatin landscape favorable for target gene transcription. Importantly, NSD2 target genes were enriched for key oncogenic pathways, and 24 transcription factors implicated in neurodevelopment and acute leukemia, consistent with its role in Wolf-Hirschhorn syndrome and MM. Eight of these transcription factors are known oncogenic drivers in acute leukemia or MM, highlighting a novel molecular mechanism for NSD2’s role in t(4;14) MM.

Differential expression between normal chr1 and gain(1q) MM patients with t(4;14) translocation

Impact of additional chromosome 1 structural events on outcome A.Effect of amp(1q) with or without a total (TT) gain on PFS B. Effect of amp(1q) on OS

Differential expression between patients with no 1q gain and those with a gain(1q:CKS1B). A. All genes that are differentially expressed

Differential expression between normal chr1 and gain(1q) MM patients with t(11;14) translocation

Methylation probe intensity across chromosome 1. Heatmap representation of the beta value for all probes across chromosome 1, the probes a presented in a genomic coordinate sorted fashion. The recurrent regions of deletion, gain, templated insertion, and chromothripsis have be highlighted along with the cytoband information for reference.

Ionizing radiotherapy (RT) is a widely used treatment strategy for malignancies. In solid tumors, RT-induced double-strand breaks lead to the accumulation of insertion-deletions (indels; ID), and their repair by nonhomologous end joining has been linked to the ID8 mutational signature in surviving cells. However, the extent of RT-induced mutagenesis in hematologic malignancies and its impact on their mutational profiles and interplay with commonly used chemotherapies has not yet been explored. In this study, we interrogated 580 whole-genome sequence (WGS) samples from patients with large B-cell lymphoma, multiple myeloma, and myeloid neoplasms and identified ID8 only in relapsed disease. Yet ID8 was detected after exposure to both RT and mutagenic chemotherapy (i.e., platinum and melphalan). Using WGS of single-cell colonies derived from treated lymphoma cells, we revealed a dose-response relationship between RT and platinum and ID8. Finally, using ID8 as a genomic barcode, we demonstrate that a single RT-surviving cell may seed distant relapse. SIGNIFICANCE:RT and the ID8 indel signature are related, but their genomic impact on hematologic malignancies is unclear. Leveraging WGS, we linked ID8 to both RT and mutagenic chemotherapy and validated that platinum can induce ID8. We used ID8 as a genomic barcode to reveal that RT-resistant cells may seed systemic relapse.

ABSTRACT:We carried out a single-cell multiomic analysis on a series of MYD88-mutated Waldenström macroglobulinemia (WM) patients and identified 2 distinct subtypes of disease, memory B-cell (MBC)-like and plasma cell (PC)-like, based on their expression of key lineage defining genes. Biologically, the subtypes are characterized by their variable capacity to differentiate fully toward a PC and exhibit unique transcriptomic, chromatin accessibility, and genomic profiles. The MBC-like subtype is unable to differentiate beyond the MBC stage, upregulates key MBC genes, and is characterized by upregulated B-cell receptor and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling. In contrast, the PC-like subtype can partially differentiate toward a PC, upregulates key PC genes, has enhanced NF-κB signaling, and has an upregulated unfolded protein response. Pseudotime trajectory analysis of combined single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin with 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 2 disease subtypes were validated further using hierarchical clustering of bulk RNA-sequencing data from a secondary set of patients. The biological significance of the subtypes was further established using whole-genome sequencing, in which 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 2 disease subtypes with distinct epigenetic, mutational, transcriptional, and clinical features, with potential implications for WM treatment strategies.

Bispecific antibodies (BsAbs) and chimeric antigen receptor T-cells (CAR-T) are T-cell engagers (TCEs) becoming increasingly important for treatment of multiple myeloma. The purpose of this paper is to review TCE side effects and their management. In doing so, we will demonstrate that outpatient delivery of TCEs can be safe and advantageous for patients and healthcare systems. The initial introduction of TCE therapy has been limited to the inpatient setting due to risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These complications, which typically occur in the first few weeks of initiating therapy, are mediated by an exaggerated inflammatory response triggered by TCE binding to tumor cells. BsAb trials have demonstrated a high overall incidence of CRS, though severe cases are rare as is development of ICANS. The incidence and severity of CRS and ICANS seem to be higher with CAR-T therapy. Predictors of development and severity of CRS and ICANS include disease bulk, lymphodepletion strategy, CAR-T construct used, and pattern of expression of the tumor antigen. Prevention strategies include step-up dosing, disease bulk reduction, prophylactic steroid use and premedication. Treatment strategies include the use of steroids and cytokine binders/blockers, such as anti-IL6 and anti-IL1 agents. Effective prophylaxis and management of CRS and ICANS has reduced the impact of these complications and opened the potential for outpatient delivery. Outpatient delivery of TCEs is possible with appropriate preventative strategies, education, and established pathways for prompt transition to inpatient management if needed.

Common dependency pathway analysis

List of dysregulated oncogenes, tumor suppressor genes, and fusion proteins in the presence or absence of gain(1q) based on the Cancer Gene Census

Multiple myeloma evolution is characterized by the accumulation of genomic drivers over time. To unravel this timeline and its impact on clinical outcomes, we analyzed 421 whole-genome sequences from 382 patients. Using clock-like mutational signatures, we estimated a time lag of two to four decades between the initiation of events and diagnosis. We demonstrate that odd-numbered chromosome trisomies in patients with hyperdiploidy can be acquired simultaneously with other chromosomal gains (for example, 1q gain). We show that hyperdiploidy is acquired after immunoglobulin heavy chain translocation when both events co-occur. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (>1 extra copy), but fared worse than those with late 1q gain. This finding underscores that the 1q gain prognostic impact depends more on the timing of acquisition than on the number of copies gained. Overall, this study contributes to a better understanding of the life history of myeloma and may have prognostic implications.

Genes with increased dependency in cell lines with del(1p) [part A] Genes with increased dependency in cell lines with del(1p) [part B]

Genes with increased dependency in cell lines with gain(1q).

Bayes Factor output between genetic variables Correlation analysis between deletion region, gain regions, and other genetic events

Recurrent regions of chromothripsis and chromoplexy together with the candidate genes located within the regions. A. CHromothripsis B. Templated Instertion