The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma.

Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IGH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing (WGS) data from 1173 MM samples. Integrating molecular time and structural variants (SV) within early chromosomal duplications, we indeed identified pre-gain deletions in 9.4% of HY patients without IGH translocations, challenging HY as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSG) and/or oncogenes in 2.4% of HY patients without IGH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to post-gain deletions as novel driver mechanisms in MM. Using multi-omics approaches to investigate their biological impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both oncogene and TSG activity, despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM.

The genomic landscape of Vk*MYC myeloma highlights shared pathways of transformation between mice and humans.

Multiple myeloma (MM) is a heterogeneous disease characterized by frequent MYC translocations. Sporadic MYC activation in the germinal center of genetically engineered Vk*MYC mice is sufficient to induce plasma cell tumors in which a variety of secondary mutations are spontaneously acquired and selected over time. Analysis of 119 Vk*MYC myeloma reveals recurrent copy number alterations, structural variations, chromothripsis, driver mutations, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational activity, and a progressive decrease in immunoglobulin transcription that inversely correlates with proliferation. Moreover, we identify frequent insertional mutagenesis by endogenous retro-elements as a murine specific mechanism to activate NF-kB and IL6 signaling pathways shared with human MM. Despite the increased genomic complexity associated with progression, advanced tumors remain dependent on MYC. In summary, here we credential the Vk*MYC mouse as a unique resource to explore MM genomic evolution and describe a fully annotated collection of diverse and immortalized murine MM tumors.

Genomic Profiling to Contextualize the Results of Intervention for Smoldering Multiple Myeloma.

PURPOSE: Early intervention for High-Risk Smoldering Multiple Myeloma (HR-SMM) achieves deep and prolonged responses. It is unclear if beneficial outcomes are due to treatment of less complex, susceptible disease or inaccuracy in clinical definition of cases entered. EXPERIMENTAL DESIGN: Here, we interrogated whole genome and whole exome sequencing for 54 patients across two HR-SMM interventional studies (NCT01572480, NCT02279394). RESULTS: We reveal that the genomic landscape of treated HR-SMM is generally simple as compared to Newly Diagnosed (ND)MM counterparts with less inactivation of tumor suppressor genes, RAS pathway mutations, MYC disruption, and APOBEC contribution. The absence of these events parallels that of indolent precursor conditions, possibly explaining overall excellent outcomes. However, some patients harboring genomic complexity fail to sustain response and experience resistant, progressive disease. Overall, clinical risk scores do not effectively discriminate between genomically indolent and aggressive disease. CONCLUSIONS: Genomic profiling can contextualize the advantage of early intervention in SMM and guide personalization of therapy.

Minimal Residual Disease-Adapted Therapy in Multiple Myeloma: Current Evidence and Opinions.

PURPOSE OF REVIEW: Multiple myeloma (MM) is a biologically heterogeneous malignancy with relatively uniform treatment paradigms. This review aims to assess the growing role of Minimal Residual Disease (MRD) assessment in facilitating response-adapted therapeutic decision making to individualize therapy in MM. RECENT FINDINGS: MRD has been repeatedly demonstrated to provide strong prognostic information, superseding traditional IMWG response criteria. The use of MRD to modulate therapy remains controversial. Here, we review the existing landscape of MRD-adapted trial designs in both induction/consolidation and maintenance settings, including recent data from influential studies and retrospective analyses. We navigate existing data, leverage the increased resolution of longitudinal MRD assessments, and comment on trials in progress to explain our current utilization of MRD in the clinic. MRD transcends traditional response assessments by providing a window into disease-treatment interaction over time. As a strong patient-level surrogate, MRD has limited current use in individualizing treatment, but is poised to comprehensively shape treatment strategies at many key points in a patient's MM course.

Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. OBJECTIVE: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. DESIGN: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. MEASUREMENTS: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. RESULTS: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. LIMITATION: The prediction model will require external validation. CONCLUSION: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. PRIMARY FUNDING SOURCE: International Myeloma Foundation and the European Research Council.

Early detection of multiple myeloma: A first step towards a screening programme.

Novel therapies for multiple myeloma have substantially improved the prognosis, but before patients are able to benefit from treatment, a diagnosis must have been made. The Myeloma UK laboratory working group has developed a three-part tool box to help primary care physicians to suspect myeloma despite mostly vague symptoms, to do the right tests and to derive the proper conclusions from the results. Commentary on: Drayson et al. Laboratory practice is central to earlier myeloma diagnosis; utilising a primary care diagnostic tool and laboratory guidelines integrated into haematology services. Br J Haematol 2024;204:476-486.

Emerging Strategies for the Prevention of Immune Toxicities Associated with T cell-Engaging Cancer Therapies.

SUMMARY: Immune-related toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common side effects of bispecific antibody and chimeric antigen receptor (CAR) T-cell therapies of hematologic malignancies. As anti-inflammatory therapy (the standard of care) is variably effective in mitigating these toxicities after onset, here we discuss emerging evidence for shifting the strategy from mitigation to prevention.

Genomic Classification and Individualized Prognosis in Multiple Myeloma.

PURPOSE: Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years. METHODS: To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data. RESULTS: Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression-based molecular classifications. To build a model predicting individualized risk in NDMM (IRMMa), we integrated clinical, genomic, and treatment variables. To correct for time-dependent variables, including high-dose melphalan followed by autologous stem-cell transplantation (HDM-ASCT), and maintenance therapy, a multi-state model was designed. The IRMMa model accuracy was significantly higher than all comparator prognostic models, with a c-index for OS of 0.726, compared with International Staging System (ISS; 0.61), revised-ISS (0.572), and R2-ISS (0.625). Integral to model accuracy was 20 genomic features, including 1q21 gain/amp, del 1p, TP53 loss, NSD2 translocations, APOBEC mutational signatures, and copy-number signatures (reflecting the complex structural variant chromothripsis). IRMMa accuracy and superiority compared with other prognostic models were validated on 256 patients enrolled in the GMMG-HD6 (ClinicalTrials.gov identifier: NCT02495922) clinical trial. Individualized patient risks were significantly affected across the 12 genomic groups by different treatment strategies (ie, treatment variance), which was used to identify patients for whom HDM-ASCT is particularly effective versus patients for whom the impact is limited. CONCLUSION: Integrating clinical, demographic, genomic, and therapeutic data, to our knowledge, we have developed the first individualized risk-prediction model enabling personally tailored therapeutic decisions for patients with NDMM.

Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden.

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore present a target population for MGUS screening. This two-part study is the first study to evaluate the relationship of MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio (OR)= 1.10; 95% confidence interval (CI): 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer associated with the progression of MGUS, except for myeloid malignancies which were associated with lower risk of progression (hazard ratio (HR)=0.37; 95%CI: 0.16-0.89; p=0.028). Our findings indicate that a prior cancer are not a significant aetiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.

Dietary risk factors for monoclonal gammopathy of undetermined significance in a racially diverse population.

ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma, is associated with shorter lifespan and cardiac, renal, neurologic, and immune-related comorbidities. There is little known about modifiable risk factors for this condition. To determine whether the risk of MGUS is associated with dietary factors in a racially diverse population, we conducted a US population-based case-control study from the National Health and Nutrition Examination Survey (1988-2004), which included 373 individuals with MGUS and 1406 matched controls. Diet was characterized by one 24-hour dietary recall, with gram intake of individual foods and beverages aggregated into groups. Unconditional multivariable logistic regressions were used to model associations between intake of several food groups and MGUS, with odds ratios (ORs) and 95% confidence intervals (CIs) reported for the highest relative to the lowest quantile of intake. Daily gram intake of several food and beverage groups were significantly associated with MGUS. MGUS was inversely associated with whole-grain bread, oats, and rice (OR, 0.70; 95% CI, 0.48-1.00; P < .05), fruits (excluding juice) and vegetables (OR, 0.69; 95% CI, 0.52-0.93; P = .02), vegetables (OR, 0.75; 95% CI, 0.56-0.99; P < .05), tomatoes (OR, 0.72; 95% CI, 0.51-1.00; P < .05), and cruciferous vegetables (OR, 0.44; 95% CI, 0.26-0.74; P < .01). Direct associations were observed for sugar-sweetened beverages (OR, 1.34; 95% CI, 1.00-1.78; P < .05), sugar-sweetened soft drinks (OR, 1.41; 95% CI, 1.01-1.96; P = .04), and artificially sweetened soft drinks (OR, 1.55; 95% CI, 1.04-2.33; P = .03). Our study shows that diet is potentially a modifiable risk factor for MGUS.

Impact of Rare Structural Variant Events in Newly Diagnosed Multiple Myeloma.

PURPOSE: Whole-genome sequencing (WGS) of patients with newly diagnosed multiple myeloma (NDMM) has shown recurrent structural variant (SV) involvement in distinct regions of the genome (i.e., hotspots) and causing recurrent copy-number alterations. Together with canonical immunoglobulin translocations, these SVs are recognized as "recurrent SVs." More than half of SVs were not involved in recurrent events. The significance of these "rare SVs" has not been previously examined. EXPERIMENTAL DESIGN: In this study, we utilize 752 WGS and 591 RNA sequencing data from patients with NDMM to determine the role of rare SVs in myeloma pathogenesis. RESULTS: Ninety-four percent of patients harbored at least one rare SV event. Rare SVs showed an SV class-specific enrichment within genes and superenhancers associated with outlier gene expression. Furthermore, known myeloma driver genes recurrently impacted by point mutations were dysregulated by rare SVs. CONCLUSIONS: Overall, we demonstrate the association of rare SVs with aberrant gene expression supporting a potential driver role in myeloma pathogenesis.

Genomic and immune determinants of resistance to anti-CD38 monoclonal antibody-based therapy in relapsed refractory multiple myeloma.

Anti-CD38 antibody therapies have transformed multiple myeloma (MM) treatment. However, a large fraction of patients inevitably relapses. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd; NCT03848676 ). Whole genome sequencing (WGS) before and after treatment pinpointed genomic drivers associated with early progression, including RPL5 loss and APOBEC mutagenesis. Flow cytometry on 202 blood samples, collected every three months until progression for 31 patients, revealed distinct immune changes significantly impacting clinical outcomes. Progressing patients exhibited significant depletion of CD38+ NK cells, persistence of T cell exhaustion, and reduced depletion of T-reg cells over time. These findings underscore the influence of immune composition and daratumumab-induced immune changes in promoting MM resistance. Integrating genomics and flow cytometry unveiled associations between adverse genomic features and immune patterns. Overall, this study sheds light on the intricate interplay between genomic complexity and the immune microenvironment driving resistance to Dara-Rd.

Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens.

Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.

Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma.

The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor ß sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure. We compare patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observe that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response.

MRD and Plasma Cell Dynamics after CAR T-cell Therapy in Myeloma.

SUMMARY: In this issue, Paiva and colleagues characterize the dynamics of minimal residual disease (MRD) and clinical responses during chimeric antigen receptor (CAR) T-cell therapy of relapsed/refractory multiple myeloma. Although both correlate with prolonged progression-free survival, MRD is reached faster in the bone marrow than complete response in peripheral blood; consequently, the study addresses the need for future guidelines to explore new MRD-negative definitions that are independent of the monoclonal (M) protein to overcome this limitation, particularly in clinical trials using early depth of response as an endpoint. See related article by Paiva et al., p. 365 (1).

The Vk*MYC Mouse Model recapitulates human multiple myeloma evolution and genomic diversity.

Despite advancements in profiling multiple myeloma (MM) and its precursor conditions, there is limited information on mechanisms underlying disease progression. Clincal efforts designed to deconvolute such mechanisms are challenged by the long lead time between monoclonal gammopathy and its transformation to MM. MM mouse models represent an opportunity to overcome this temporal limitation. Here, we profile the genomic landscape of 118 genetically engineered Vk*MYC MM and reveal that it recapitulates the genomic heterogenenity and life history of human MM. We observed recurrent copy number alterations, structural variations, chromothripsis, driver mutations, APOBEC mutational activity, and a progressive decrease in immunoglobulin transcription that inversely correlates with proliferation. Moreover, we identified frequent insertional mutagenesis by endogenous retro-elements as a murine specific mechanism to activate NF-kB and IL6 signaling pathways shared with human MM. Despite the increased genomic complexity associated with progression, advanced tumors remain dependent on MYC expression, that drives the progression of monoclonal gammopathy to MM.

Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma.

B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.

Bortezomib, lenalidomide and dexamethasone (VRd) vs carfilzomib, lenalidomide and dexamethasone (KRd) as induction therapy in newly diagnosed multiple myeloma.

Lenalidomide and dexamethasone with bortezomib (VRd) or carfilzomib (KRd) are commonly used induction regimens in the U.S. This single-center, retrospective study evaluated outcomes and safety of VRd and KRd. Primary endpoint was progression-free survival (PFS). Of 389 patients with newly diagnosed multiple myeloma, 198 received VRd and 191 received KRd. Median PFS was not reached (NR) in both groups; 5-year PFS was 56% (95%CI, 48-64%) for VRd and 67% (60-75%) for KRd (P = 0.027). Estimated 5-year EFS was 34% (95%CI, 27-42%) for VRd and 52% (45-60%) for KRd (P < 0.001) with corresponding 5-year OS of 80% (95%CI, 75-87%) and 90% (85-95%), respectively (P = 0.053). For standard-risk patients, 5-year PFS was 68% (95%CI, 60-78%) for VRd and 75% (65-85%) for KRd (P = 0.20) with 5-year OS of 87% (95%CI, 81-94%) and 93% (87-99%), respectively (P = 0.13). For high-risk patients, median PFS was 41 months (95%CI, 32.8-61.1) for VRd and 70.9 months (58.2-NR) for KRd (P = 0.016). Respective 5-year PFS and OS were 35% (95%CI, 24-51%) and 69% (58-82%) for VRd and 58% (47-71%) and 88% (80-97%, P = 0.044) for KRd. Overall, KRd resulted in improved PFS and EFS with a trend toward improved OS compared to VRd with associations primarily driven by improvements in outcome for high-risk patients.

Disease associations with monoclonal gammopathy of undetermined significance can only be evaluated using screened cohorts: results from the population-based iStopMM study.

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been associated with other medical conditions. Since systematic screening is not recommended, MGUS is typically diagnosed due to underlying diseases and most cases are not diagnosed. Most previous studies on MGUS disease associations have been based on clinical cohorts, possibly resulting in selection bias. Here we estimate this selection bias by comparing clinically diagnosed and screened individuals with MGUS with regards to demographics, laboratory features, and comorbidities. A total of 75,422 participants in the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study were screened for MGUS by serum protein electrophoresis, immunofixation and free light chain assay (clinicaltrials gov. Identifier: NCT03327597). We identified 3,352 individuals with MGUS, whereof 240 had previously been clinically diagnosed (clinical MGUS), and crosslinked our data with large, nationwide registries for information on comorbidities. Those with clinical MGUS were more likely to have at least one comorbidity (odds ratio=2.24; 95% confidence interval: 1.30-4.19), and on average had more comorbidities than the screened MGUS group (3.23 vs. 2.36, mean difference 0.68; 95% confidence interval: 0.46-0.90). They were also more likely to have rheumatological disease, neurological disease, chronic kidney disease, liver disease, heart failure, or endocrine disorders. These findings indicate that individuals with clinical MGUS have more comorbidities than the general MGUS population and that previous studies have been affected by significant selection bias. Our findings highlight the importance of screening data when studying biological and epidemiological implications of MGUS.

Multiomic Mapping of Acquired Chromosome 1 Copy-Number and Structural Variants to Identify Therapeutic Vulnerabilities in Multiple Myeloma.

PURPOSE: Chromosome 1 (chr1) copy-number abnormalities (CNA) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and are associated with a heterogeneous impact on outcomes, the drivers of which are largely unknown. EXPERIMENTAL DESIGN: A multiomic approach comprising CRISPR, gene mapping of CNAs and SVs, methylation, expression, and mutational analysis was used to document the extent of chr1 molecular variants and their impact on pathway utilization. RESULTS: We identified two distinct groups of gain(1q): focal gains associated with limited gene-expression changes and a neutral prognosis, and whole-arm gains, which are associated with substantial gene-expression changes, complex genetics, and an adverse prognosis. CRISPR identified a number of dependencies on chr1 but only limited variants associated with acquired CNAs. We identified seven regions of deletion, nine of gain, three of chromothripsis (CT), and two of templated insertion (TI), which contain a number of potential drivers. An additional mechanism involving hypomethylation of genes at 1q may contribute to the aberrant gene expression of a number of genes. Expression changes associated with whole-arm gains were substantial and gene set enrichment analysis identified metabolic processes, apoptotic resistance, signaling via the MAPK pathway, and upregulation of transcription factors as being key drivers of the adverse prognosis associated with these variants. CONCLUSIONS: Multiple layers of genetic complexity impact the phenotype associated with CNAs on chr1 to generate its associated clinical phenotype. Whole-arm gains of 1q are the critically important prognostic group that deregulate multiple pathways, which may offer therapeutic vulnerabilities.