Comparison of progression risk of monoclonal gammopathy of undetermined significance by method of detection.

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic pre-malignant disorder. The current standard of care is not to screen for MGUS, so it is often incidentally diagnosed in the clinic. It is unknown whether the outcomes of screened versus clinically detected MGUS differ. We compared the progression risk between screened versus clinical MGUS cohorts and assessed whether the MGUS detection method impacted risk prediction of established clinical factors (score). We included 379 screened MGUS from the Olmsted County population based study and 1384 MGUS patients diagnosed during routine clinical evaluation at Mayo Clinic. Median follow-up time for the screened versus clinical cohort was 26.6 and 40.1 years, respectively. Accounting for death as a competing risk, the cumulative incidence of progression at 25 years was similar in the screened (11.1% [95% CI 8.3-14.8]) versus clinical (10.1% [95% CI 8.6-11.8%]) MGUS cohorts, even when stratified by sex, age, or the baseline MGUS risk score. Overall, 0.9 (95% CI 0.6-1.2) screened versus 1.0 (95% CI 0.9-1.2) clinically detected MGUS patients experienced disease progression for every 100 person years of follow-up. MGUS detection method did not modify the association between MGUS risk score and progression risk (pinteraction=0.217) and did not add to known risk factors for progression (likelihood ratio test, p=0.839). Here we show that progression risk among patients with screened versus clinically detected heavy-chain MGUS was similar. Future studies are needed to assess if tailored follow-up of screened MGUS patients affects clinical outcomes.

Dexamethasone dose intensity does not impact outcomes in newly diagnosed multiple myeloma: a secondary SWOG analysis.

Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM) despite common toxicities including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 milligrams (mg) once weekly was associated with lower mortality than higher doses of dexamethasone. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM have not been fully characterized. We conducted a secondary pooled analysis of the S0777 and S1211 SWOG studies of NDMM, which employed lenalidomide-dexamethasone (Rd) alone with or without bortezomib (VRd) and with or without elotuzumab (Elo-VRd). Planned dexamethasone intensity was 40-60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for Grade 3+ toxicities per both study protocols). Of 541 evaluated patients, the LD-DEX group comprised 373 patients (69%). There was no difference in PFS or OS between the FD-DEX or LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in multivariate models were treatment arm, age ≥70, and thrombocytopenia; FD-DEX did not significantly improve either outcome. Our study suggests that dexamethasone dose reductions are common in multiple myeloma, even within clinical trials. Given dexamethasone's many toxicities and unclear benefit in the era of modern treatment regimens, dexamethasone dose reduction during NDMM induction warrants further prospective study. NCT00644228, NCT01668719.

Prognostic impact of cytogenetic abnormalities by FISH in AL amyloidosis with daratumumab-based frontline therapy.

We performed an international retrospective cohort study to investigate the prognostic impact of cytogenetic abnormalities by FISH in 283 patients with AL amyloidosis treated with frontline daratumumab-bortezomib-cyclophosphamide-dexamethasone (Dara-VCD) or Dara-VD. The cytogenetic subgroups of interest were t(11;14), gain/amp(1q) [hereafter, +1q], hyperdiploidy, deletion(13q), del(17p), and myeloma high-risk (HR) translocations (t[4;14], t[14;16], or t[14;20]). The endpoints of interest were rate of hematologic complete response (heme CR), very good partial response or better (≥VGPR), and hematologic event-free survival (Heme EFS). The incidence of abnormalities was following: t(11;14)-53.4%; deletion (13q)-28.9%; +1q-22.3%; hyperdiploidy-19.4%; HR translocations-6.6%; and deletion(17p)-4.5%. The heme-CR rate by cytogenetic subgroups were: t(11;14) vs no t(11;14)-45.2% vs 41.8% (p=0.597); del(13q) vs no del(13q)-46.8% vs 42.8% (p=0.594); +1q vs no +1q-30.2% vs 47.9% (p=0.022); hyperdiploidy vs no hyperdiploidy-39.5% vs 44.9% (p=0.541); HR translocations vs none: 45.5% vs 43.1% (p=0.877); and del(17p) vs no del(17p)-50.0% vs 42.9% respectively (p=0.658). Similarly, +1q was the only subgroup with a significantly lower ≥VGPR rate (64.2% vs 79.0%; p=0.033). At a median follow-up of 19.8 months, the median heme-EFS was 49.6 months (95% CI, 24.7-not reached [NR]), and the 2-year OS was 80.98% (95% CI, 75.6-85.4). The presence of+1q was significantly associated with worse heme-EFS on multivariate analysis (HR 2.06, 95% CI, 1.14-3.71; p=0.017). Notably, there was no adverse prognostic impact of t(11;14) on heme EFS or OS. In conclusion, +1q is associated with worse outcome in the daratumumab-era. Clinical trials testing novel immunotherapies frontline should be enriched in +1q to further improve outcomes in this subgroup.

Impact of cytogenetic abnormalities on the risk of disease progression in solitary bone plasmacytomas.

Most patients with solitary bone plasmacytomas (SBP) progress to multiple myeloma (MM) after definitive radiation therapy as their primary treatment. Whether the presence of high-risk (HR) cytogenetic abnormalities by fluorescence in situ hybridization (FISH) in the clonal plasma cells, obtained either directly from the diagnostic SBP tissue or the corresponding bone marrow examination at the time of diagnosis, is associated with a shorter time to progression (TTP) to MM is unknown. This study evaluated all patients diagnosed with SBP at the Mayo Clinic from January 2012 to July 2022. The presence of del(17p), t(14;16), t(4;14), or +1q (gain or amplification) by FISH in clonal plasma cells was defined as HR. A total of 114 patients were included in this cohort, and baseline FISH was available for 55 patients (48%), of which 22 were classified as HR (40%). The median TTP to MM for patients with SBP and HR FISH was 8 months (95% confidence interval [CI], 6.3-26) compared with 42 months (95% CI, 25-not reached [NR]) in patients with SBP without HR FISH (P < .001). In a multivariate analysis, only HR FISH was a significant predictor for shorter TTP to MM, independent of minimal marrow involvement and an abnormal serum free light chain ratio at diagnosis. Deletion (17p) and gain 1q abnormalities were the most common FISH abnormalities responsible for the short TTP to MM. Thus, assessing for HR FISH abnormalities in clonal plasma cells derived from either the diagnostic SBP tissue or the staging bone marrow examination of patients with newly diagnosed SBP is feasible and prognostic for a shorter TTP to MM.

Consensus guidelines and recommendations for the management and response assessment of chimeric antigen receptor T-cell therapy in clinical practice for relapsed and refractory multiple myeloma: a report from the International Myeloma Working Group Immunotherapy Committee.

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in patients with late-line refractory multiple myeloma, with response rates ranging from 73 to 98%. To date, three products have been approved: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which are approved by the US Food and Drug Administration, the European Medicines Agency, Health Canada (ide-cel only), and Brazil ANVISA (cilta-cel only); and equecabtagene autoleucel (eque-cel), which was approved by the Chinese National Medical Products Administration. CAR T-cell therapy is different from previous anti-myeloma therapeutics with unique toxic effects that require distinct mitigation strategies. Thus, a panel of experts from the International Myeloma Working Group was assembled to provide guidance for clinical use of CAR T-cell therapy in myeloma. This consensus opinion is from experts in the field of haematopoietic cell transplantation, cell therapy, and multiple myeloma therapeutics.

The effect of neighborhood socioeconomic disadvantage on smoking status, quit attempts, and receipt of cessation support among adults with cancer: Results from nine ECOG-ACRIN Cancer Research Group trials.

BACKGROUND: Tobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer. METHODS: A modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) was administered to patients enrolled in nine ECOG-ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression. RESULTS: A total of 740 patients completing the C-TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69-7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64-10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02-0.58; p = .0086) versus those in the least disadvantaged neighborhoods. CONCLUSIONS: Greater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.

Sustained minimal residual disease negativity in newly diagnosed multiple myeloma and the impact of daratumumab in MAIA and ALCYONE.

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE).

Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA.

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10-5 sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172.

The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee.

Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Adjusting for subsequent therapies in the TOURMALINE-MM1 study shows clinically meaningful improvement in overall survival with addition of ixazomib to lenalidomide and dexamethasone.

TOURMALINE-MM1, the only blinded randomized study in patients with relapsed and/or refractory multiple myeloma (RRMM; ≥1 prior therapy) in the last 10 years, investigated ixazomib + lenalidomide + dexamethasone (IRd) versus lenalidomide + dexamethasone (Rd). Final overall survival (OS) data were based on a median follow-up of 85 months. In RRMM trials where patients have had 1-3 relapses after initial treatment, a high proportion receive subsequent therapy. Application of salvage therapies in blinded trials and newer modes of therapy can increasingly complicate the interpretation of OS. This analysis explores the impact of subsequent therapies on OS outcomes in TOURMALINE-MM1. The inverse probability of censoring weights (IPCW) method, marginal structural model (MSM), and rank-preserving structural failure time model (RPSFTM) were utilized to adjust for confounding on OS, introduced by subsequent therapies. Analyses were conducted for the intent-totreat (ITT) population and ≥2 prior lines subgroup. Unadjusted hazard ratio (HR) for IRd versus Rd was 0.94 (95% confidence interval [CI]: 0.78-1.13) in the ITT population. After adjusting for the impact of subsequent therapies by the RPSFTM method, estimated HR for IRd versus Rd in the ITT population was 0.89 (95% CI: 0.74-1.07). Adjusting with IPCW and MSM methods also showed an improvement in HR, favoring IRd. IRd may be particularly beneficial in patients with ≥2 prior lines of therapy (IPCW and MSM HR=0.52, 95% CI: 0.30-0.88; RPSFTM HR=0.68, 95% CI: 0.51-0.91). These analyses highlight the growing challenge of demonstrating OS benefit in MM patients and the importance of assessing confounding introduced by subsequent therapies when interpreting OS.

Comparing the clinical trial efficacy versus real-world effectiveness of treatments for multiple myeloma: a population-based study.

Not available.

Progression-free survival as a surrogate endpoint for overall survival in patients with relapsed or refractory multiple myeloma.

OBJECTIVES: The goal of the research was to assess the quantitative relationship between median progression-free survival (PFS) and median overall survival (OS) specifically among patients with relapsed/refractory multiple myeloma (RRMM) based on published randomized controlled trials (RCTs). METHODS: Two bibliographic databases (PubMed and Embase, 1970-2017) were systematically searched for RCTs in RRMM that reported OS and PFS, followed by an updated search of studies published between 2010 and 2022 in 3 databases (Embase, MEDLINE, and EBM Reviews, 2010-2022). The association between median PFS and median OS was assessed using the nonparametric Spearman rank and parametric Pearson correlation coefficients. Subsequently, the quantitative relationship between PFS and OS was assessed using weighted least-squares regression adjusted for covariates including age, sex, and publication year. Study arms were weighted by the number of patients in each arm. RESULTS: A total of 31 RCTs (56 treatment arms, 10,450 patients with RRMM) were included in the analysis. The average median PFS and median OS were 7.1 months (SD 5.5) and 28.1 months (SD 11.8), respectively. The Spearman and Pearson correlation coefficients between median PFS and median OS were 0.80 (P < 0.0001) and 0.79 (P < 0.0001), respectively. In individual treatment arms of RRMM trials, each 1-month increase in median PFS was associated with a 1.72-month (95% CI 1.26-2.17) increase in median OS. CONCLUSION: Analysis of the relationship between PFS and OS incorporating more recent studies in RRMM further substantiates the use of PFS to predict OS in RRMM.

Venetoclax in biomarker-selected multiple myeloma patients: Impact of exposure on clinical efficacy and safety.

Venetoclax, a potent BCL-2 inhibitor, is currently under development for treatment of t(11;14) Multiple myeloma (MM). The objective of this research was to investigate the exposure-response relationships of venetoclax for a phase 1/2 study evaluating venetoclax monotherapy or in combination with dexamethasone in relapsed or refractory MM. A total of 117 patients receiving venetoclax at 300, 600, 800, 900, or 1200 mg were included in the analysis. The impact of venetoclax exposures on efficacy (objective response rate [ORR], progression-free survival [PFS] and overall survival [OS]) as well as safety (treatment-emergent adverse effects (grade ≥3) of neutropenia, infection, and any grade of serious treatment-emergent adverse effects) was evaluated. In the t(11;14)-positive subpopulation, venetoclax exposure relationships to PFS and OS indicated a trend of longer PFS and OS with higher exposures. Moreover, logistic regression analyses for clinical response (ORR and ≥VGPR rate) demonstrated a statistically significant (p < 0.05) relationship with exposure. Evaluation of the exposure-safety relationships demonstrated a lack of a relationship between venetoclax exposures (AUCavg ) and grade ≥3 infections, grade ≥3 neutropenia, grade ≥3 treatment-emergent adverse events or any grade serious treatment-emergent adverse events. These findings support further study of venetoclax at 800 mg QD dose in combination with dexamethasone in the t(11;14)-positive patient population where increased efficacy was observed without an increase in safety events.Clinical Trial: NCT01794520 registered 20 February 2013.

Thromboprophylaxis in multiple myeloma: a case-based review with practical guidelines.

Venous thromboembolism (VTE) poses a significant challenge in the context of multiple myeloma, with an incidence of up to 10% in newly diagnosed patients and varying frequency in the relapsed/refractory setting. Accurate VTE risk assessment and personalized thromboprophylaxis strategies are important parts of supportive care in myeloma. There are three validated risk assessment models for prediction of VTE risk in newly diagnosed myeloma-SAVED, IMPEDE-VTE, and PRISM. In this review, we delve into the practical applications of VTE risk prediction models in the context of current therapies. By emphasizing the necessity of a tailored approach, we underscore the importance of considering patient-specific, disease-specific, and treatment-specific risk factors in each clinical scenario, and using that data to complement the output from risk assessment models. We also provide a summary of currently available data on VTE thromboprophylaxis in myeloma, and highlight specific situations where direct oral anticoagulants should be strongly considered. Our objective is to fill the critical gaps in VTE prophylaxis and management through the analysis of specific patient cases and provide a practical overview for clinicians.

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

Differences in the proteome within extracellular vesicles between premalignant and malignant plasma cell disorders.

BACKGROUND: Precursor plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) always precede the development of active malignancies such as multiple myeloma (MM). There is a need for novel biomarkers to identify those patients with such precursor plasma cell disorders who rapidly progress to MM. Plasma-derived extracellular vesicles (EVs) may serve as a reservoir of potential biomarkers that can shed light on the pathogenesis and disease biology of MM. METHODS: This study isolated small EVs (SEVs) and large EVs (LEVs) from the platelet-poor peripheral blood plasma of MGUS (n = 9) and MM (n = 12) patients using the size exclusion chromatography-based method and evaluated their proteome using a label-free proteomics workflow. RESULTS: In total, 2055 proteins were identified in SEVs, while 2794 proteins were identified in LEVs. The transferrin receptor (or CD71) protein was upregulated in both populations of EVs derived from MM patients compared to MGUS patients and was of prognostic significance. Similarly, three isoforms of serum amyloid A (SAA) protein, SAA1, SAA2, and SAA4, were also highly upregulated in SEVs within MM patients relative to MGUS patients. Finally, CD40 expression was also higher in the LEVs derived from MM patients than in MGUS patients. CONCLUSIONS: This study demonstrates the feasibility of successfully isolating both SEVs and LEVs from the peripheral blood of patients with plasma cell disorders and quantifying protein biomarkers within these EVs that could be of prognostic and diagnostic interest.

High-risk multiple myeloma: Redefining genetic, clinical, and functional high-risk disease in the era of molecular medicine and immunotherapy.

Multiple myeloma (MM) exhibits significant heterogeneity in its presentation, genetics, and treatment response. Despite therapeutic advances, some patients continue to relapse early (ER, <18-months) and rapidly cycle through therapies. Myriad prognostic factors have been identified and incorporated into risk stratification models; however, these produce discordant, often three-tiered outputs that fail to identify many patients destined for ER. Treatment strategies are increasingly focused on disease biology and trials enriched for high-risk (HR)MM, but consensus on the minimum required testing and a succinct, specific, and clinically meaningful definition for HRMM remains elusive. We review the risk-factors, definitions, and future directions for HRMM.

Three-dimensional telomere profiling predicts risk of progression in smoldering multiple myeloma.

Smoldering multiple myeloma (SMM) is a precursor stage that precedes multiple myeloma (MM). SMM is heterogenous with nearly 40% of patients progressing to MM in the first 5 years. The high rate of progression of SMM patients highlights the need for early intervention, which underscores the importance of identifying SMM patients with the highest risk of progression. Several risk stratification models showed utility in identifying high-risk SMM patients; however, these systems showed limited sensitivity. To date, identifying high-risk SMM patients remains an important clinical need. In this study, we present the 3-dimensional telomere profiling as a structural biomarker capable of stratifying SMM patients as a function of genomic instability. Quantifying telomere dysfunction using the TeloView technology showed utility in risk stratification of cancer patients, particularly hematological malignancies. In this study, we analyzed 168 SMM patients. We report an AUC in ROC analysis of 0.8 using a subset of the patients as a training dataset. We then conducted a blind validation on a different cohort and demonstrated a positive predictive value of 85% and negative predictive value of 73%, with sensitivity and specificity of 83% and 76%, respectively. We examined the correlation between the TeloView prediction and the 20-2-20 scoring system, and cytogenetic abnormalities. We report a correlation of 53% with the 20-2-20 scores and over 60% correlation with cytogenetic abnormalities. The result of this study presents the telomere profiling as an effective biomarker able to stratify SMM patients to their respective risk groups with high sensitivity and specificity.

Whole-body low-dose computed tomography in patients with newly diagnosed multiple myeloma predicts cytogenetic risk: a deep learning radiogenomics study.

OBJECTIVE: To develop a whole-body low-dose CT (WBLDCT) deep learning model and determine its accuracy in predicting the presence of cytogenetic abnormalities in multiple myeloma (MM). MATERIALS AND METHODS: WBLDCTs of MM patients performed within a year of diagnosis were included. Cytogenetic assessments of clonal plasma cells via fluorescent in situ hybridization (FISH) were used to risk-stratify patients as high-risk (HR) or standard-risk (SR). Presence of any of del(17p), t(14;16), t(4;14), and t(14;20) on FISH was defined as HR. The dataset was evenly divided into five groups (folds) at the individual patient level for model training. Mean and standard deviation (SD) of the area under the receiver operating curve (AUROC) across the folds were recorded. RESULTS: One hundred fifty-one patients with MM were included in the study. The model performed best for t(4;14), mean (SD) AUROC of 0.874 (0.073). The lowest AUROC was observed for trisomies: AUROC of 0.717 (0.058). Two- and 5-year survival rates for HR cytogenetics were 87% and 71%, respectively, compared to 91% and 79% for SR cytogenetics. Survival predictions by the WBLDCT deep learning model revealed 2- and 5-year survival rates for patients with HR cytogenetics as 87% and 71%, respectively, compared to 92% and 81% for SR cytogenetics. CONCLUSION: A deep learning model trained on WBLDCT scans predicted the presence of cytogenetic abnormalities used for risk stratification in MM. Assessment of the model's performance revealed good to excellent classification of the various cytogenetic abnormalities.

A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk.

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10-8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10-7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.