Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study.

BACKGROUND: Multicancer early detection (MCED) blood tests can detect a cancer signal from circulating cell-free DNA (cfDNA). PATHFINDER was a prospective cohort study investigating the feasibility of MCED testing for cancer screening. METHODS: In this prospective cohort study done in oncology and primary care outpatient clinics at seven US health networks, a convenience sample of adults aged 50 years or older without signs or symptoms of cancer consented to MCED testing. We collected blood, analysed cfDNA, and returned results to participants' doctors. If a methylation signature indicative of cancer was detected, predicted cancer signal origin(s) informed diagnostic assessment. The primary outcome was time to, and extent of, diagnostic testing required to confirm the presence or absence of cancer. This trial is registered at ClinicalTrials.gov, NCT04241796, and is completed. FINDINGS: Between Dec 12, 2019, and Dec 4, 2020, we recruited 6662 participants. 4204 (63·5%) of 6621 participants with analysable results were women, 2417 (36·5%) were men, and 6071 (91·7%) were White. A cancer signal was detected in 92 (1·4%) of 6621 participants with analysable results. 35 (38%) participants were diagnosed with cancer (true positives) and 57 (62%) had no cancer diagnosis (false positives). Excluding two participants whose diagnostic assessments began before MCED test results were reported, median time to diagnostic resolution was 79 days (IQR 37-219): 57 days (33-143) in true-positive and 162 days (44-248) in false-positive participants. Most participants had both laboratory tests (26 [79%] of 33 with true-positive results and 50 [88%] of 57 with false-positive results) and imaging (30 [91%] of 33 with true-positive results and 53 [93%] of 57 with false-positive results). Fewer procedures were done in participants with false-positive results (17 [30%] of 57) than true-positive results (27 [82%] of 33) and few had surgery (one with a false-positive result and three with a true-positive result). INTERPRETATION: This study supports the feasibility of MCED screening for cancer and underscores the need for further research investigating the test's clinical utility. FUNDING: GRAIL.

Prediagnosis dietary pattern and survival in patients with multiple myeloma.

Inflammation and endogenous growth factors are important in multiple myeloma (MM) pathogenesis. Although diets that modulate these biologic pathways may influence MM patient survival, studies have not examined the association of dietary patterns with MM survival. We conducted pooled prospective survival analyses of 423 MM patients from the Nurses' Health Study (1986-2016) and the Health Professionals Follow-up Study (1988-2016) using Cox regression models. We used data from repeated food frequency questionnaires (FFQ) to compute dietary patterns as of the last prediagnosis FFQ, including the Alternate Healthy Eating Index (AHEI)-2010, alternate Mediterranean Diet, Dietary Approaches to Stop Hypertension, Prudent, Western and empirical dietary inflammatory patterns and empirical dietary indices for insulin resistance and hyperinsulinemia. During follow-up, we documented 295 MM-related deaths among 345 total deaths. MM-specific mortality was 15-24% lower per one standard deviation (SD) increase (e.g., toward healthier habits) in favorable dietary pattern scores. For example, the multivariable-adjusted hazard ratio [HR] and 95% confidence interval [CI] per 1-SD increase in AHEI-2010 score were 0.76, 0.67-0.87 (p < 0.001). In contrast, MM-specific mortality was 16-24% higher per 1-SD increase (e.g., toward less healthy habits) in "unhealthy" diet scores; for example, the multivariable-adjusted HR, 95% CI per 1-SD increase in Western pattern score were 1.24, 1.07-1.44 (p = 0.005). Associations were similar for all-cause mortality. In conclusion, our consistent findings for multiple dietary patterns provide the first evidence that MM patients with healthier prediagnosis dietary habits may have longer survival than those with less healthy diets.

Research-based PAM50 signature and long-term breast cancer survival.

PURPOSE: Multi-gene signatures provide biological insight and risk stratification in breast cancer. Intrinsic molecular subtypes defined by mRNA expression of 50 genes (PAM50) are prognostic in hormone-receptor positive postmenopausal breast cancer. Yet, for 25-40% in the PAM50 intermediate risk group, long-term risk remains uncertain. Our study aimed to (i) test the long-term prognostic value of the PAM50 signature in pre- and post-menopausal breast cancer; (ii) investigate if the PAM50 model could be improved by addition of other mRNAs implicated in oncogenesis. METHODS: We used archived FFPE samples from 1723 breast cancer survivors; high quality reads were obtained on 1253 samples. Transcript expression was quantified using a custom codeset with probes for > 100 targets. Cox models assessed gene signatures for breast cancer relapse and survival. RESULTS: Over 15 + years of follow-up, PAM50 subtypes were (P < 0.01) associated with breast cancer outcomes after accounting for tumor stage, grade and age at diagnosis. Results did not differ by menopausal status at diagnosis. Women with Luminal B (versus Luminal A) subtype had a > 60% higher hazard. Addition of a 13-gene hypoxia signature improved prognostication with > 40% higher hazard in the highest vs lowest hypoxia tertiles. CONCLUSIONS: PAM50 intrinsic subtypes were independently prognostic for long-term breast cancer survival, irrespective of menopausal status. Addition of hypoxia signatures improved risk prediction. If replicated, incorporating the 13-gene hypoxia signature into the existing PAM50 risk assessment tool, may refine risk stratification and further clarify treatment for breast cancer.

The effects of weight loss and metformin on cognition among breast cancer survivors: Evidence from the Reach for Health study.

OBJECTIVE: Breast cancer survivors experience problems with cognition that interfere with daily life and can last for years. In the general population, obesity and diabetes are risk factors for cognitive decline, and weight loss can improve cognition; however, the impact of intentional weight loss on cancer survivors' cognition has not been tested. We investigated the impact of weight loss and metformin on changes in cognitive function in a sample of breast cancer survivors. METHODS: Overweight/obese postmenopausal breast cancer survivors (n = 333) were randomized to a weight loss intervention versus control and metformin versus placebo in a 2 × 2 factorial design. Outcomes were changes in five cognitive domains from baseline to 6 months measured by objective neurocognitive tests. RESULTS: There were no statistically significant intervention effects for the metformin or weight loss interventions in five neurocognitive domains. Baseline body mass index (BMI) was a significant effect modifier of the changes in verbal functioning for the weight loss (P = 0.009) and metformin interventions (P = 0.0125). These effect modifications were independent of percent weight loss achieved during the 6-month study period. CONCLUSIONS: This randomized controlled trial of weight loss and metformin interventions that examined changes to cognition among breast cancer survivors suggests that these interventions may not improve cognitive functioning among breast cancer survivors in general. However, weight loss may improve verbal functioning among individuals with a higher BMI.

Dimensions of sedentary behavior and objective cognitive functioning in breast cancer survivors.

PURPOSE: To examine associations between dimensions of sedentary behavior and cognitive function in breast cancer survivors. METHODS: Sedentary behavior variables were measured using thigh-worn activPALs, and included total daily sitting time, time in long sitting bouts, sit-to-stand transitions, and standing time. Cognitive function was assessed using the NIH Toolbox Cognitive Domain. Separate multivariable linear regression models were used to examine associations between sedentary behavior variables with the cognitive domain scores of attention, executive functioning, episodic memory, working memory, and information processing speed. RESULTS: Thirty breast cancer survivors with a mean age of 62.2 (SD = 7.8) years who were 2.6 (SD = 1.1) years since diagnosis completed study assessments. In multivariable linear regression models, more time spent standing was associated with faster information processing (b: 5.78; p = 0.03), and more time spent in long sitting bouts was associated with worse executive function (b: -2.82; p = 0.02), after adjustment for covariates. No other sedentary behavior variables were statistically significantly associated with the cognitive domains examined in this study. CONCLUSIONS: Two important sedentary constructs that are amenable to intervention, including time in prolonged sitting bouts and standing time, may be associated with cognitive function in breast cancer survivors. More research is needed to determine whether modifying these dimensions of sedentary behavior will improve cognitive function in women with a history of breast cancer, or prevent it from declining in breast cancer patients.

Body mass index throughout adulthood, physical activity, and risk of multiple myeloma: a prospective analysis in three large cohorts.

BACKGROUND: Obesity is the only known modifiable multiple myeloma (MM) risk factor. However, the influence of obesity in earlier or later adulthood and the role of other energy balance correlates in MM development are unclear. METHODS: We leveraged repeatedly updated data from the Nurses' Health Study, Health Professionals Follow-up Study, and Women's Health Study cohorts to further explore energy balance measures in MM etiology. Exposures derived from questionnaires included young adult body mass index (BMI), cumulative average BMI, BMI change since young adulthood, and cumulative average physical activity and walking. We assessed MM risk related to those variables with Cox proportional hazard models. RESULTS: We observed 575 incident MM cases in over five million person-years of follow-up across the cohorts. In pooled analyses, MM risk increased 17% per 5 kg/m2 increase in cumulative average BMI (95% confidence interval (CI): 1.05, 1.29) and 28% per 5 kg/m2 increase in young adult BMI (CI: 1.12, 1.47); adjustment for BMI change since young adulthood did not affect either association. BMI change since young adulthood and cumulative average physical activity and walking were not significantly associated with MM risk. CONCLUSIONS: These findings suggest that a high BMI in early and later adulthood are risk factors for MM.

Mediators of a physical activity intervention among women with a family history of breast cancer.

The current study examined mediators of an efficacious physical activity intervention. Women with a mean age of 42.6 (range 23-61) years and a family history of breast cancer were randomized to either an Internet-based physical activity intervention (n = 28) or an active control condition (n = 27) for three months. Data were collected between November 2010 and August 2011. Hypothesized mediators were examined using a product of coefficients model with bootstrapped standard errors. Significant mediation was observed for both self-efficacy and behavioral processes. Specifically, the regression coefficients of the indirect effects ("ab path": unstandardized effect of the intervention on physical activity that occurred through the mediator) were ab = 38.58 (95% confidence interval [CI]: 8.66-92.76) for self-efficacy, and ab = 42.02 (95% CI: 6.76-104.84) for behavioral processes. Other factors examined in this study, including cognitive processes, decisional balance, and perceived risk of breast cancer, were not statistically significant mediators. Findings suggest that self-efficacy and behavioral processes may be key constructs to use in targeting future physical activity interventions among women with a family history of breast cancer.

Sleep duration and breast cancer prognosis: perspectives from the Women's Healthy Eating and Living Study.

PURPOSE: To examine whether baseline sleep duration or changes in sleep duration are associated with breast cancer prognosis among early-stage breast cancer survivors in the multi-center Women's Healthy Eating and Living Study. METHODS: Data were collected from 1995 to 2010. Analysis included 3047 women. Sleep duration was self-reported at baseline and follow-up intervals. Cox proportional hazard models were used to investigate whether baseline sleep duration was associated with breast cancer recurrence, breast cancer-specific mortality, and all-cause mortality. Time-varying models investigated whether changes in sleep duration were associated with breast cancer prognosis. RESULTS: Compared to women who slept 7-8 h/night at baseline, sleeping ≥9 h/night was associated with a 48% increased risk of breast cancer recurrence (Hazard ratio [HR] 1.48, 95% Confidence interval [CI] 1.01, 2.00), a 52% increased risk of breast cancer-specific mortality (HR 1.52, 95% CI 1.09, 2.13), and a 43% greater risk of all-cause mortality (HR 1.43, 95% CI 1.07, 1.92). Time-varying models showed analogous increased risk in those who inconsistently slept ≥9 h/night (all P < 0.05), but not in those who consistently slept ≥9 h/night. CONCLUSIONS: Consistent long or short sleep, which may reflect inter-individual variability in the need for sleep, does not appear to influence prognosis among early-stage breast cancer survivors.

Objectively measured sedentary behavior and quality of life among survivors of early stage breast cancer.

PURPOSE: This study examined relationships between sedentary behavior accumulated in different bout durations and quality of life (QoL) among breast cancer survivors. METHODS: Postmenopausal breast cancer survivors completed the Short Form Health Survey to assess QoL and wore an accelerometer to measure sedentary behavior and physical activity between August 2011 and May 2013. RESULTS: Participants (n = 134) averaged 509.7 min/day in sedentary time with 285.2 min/day in short bouts (<20 min) and 224.5 min/day long bouts (≥20 min). Linear regression models indicated that greater total sedentary time was significantly associated with worse physical QoL (b = -0.70, p = 0.02) but not mental QoL (p = 0.92). Models that examined the accumulation of sedentary time in short bouts and long bouts together showed that time in long sedentary bouts was significantly related to physical QoL (b = -0.72, p = 0.02), while time in short bouts was not (p = 0.63). Moderate-to-vigorous intensity physical activity (MVPA) was a significant effect modifier of the relation between time spent in long sedentary bouts and physical QoL (p = 0.028) such that greater time in long bouts was associated with worse physical QoL only among women with lower levels of MVPA. CONCLUSIONS: Findings indicate that time spent in long sedentary bouts is associated with worse physical QoL among breast cancer survivors who do not engage in high levels of MVPA. Future research should examine reducing sedentary time as a potential strategy to improve physical QoL.

Impact of very low physical activity, BMI, and comorbidities on mortality among breast cancer survivors.

The purpose of this study was to examine post-diagnosis BMI, very low physical activity, and comorbidities, as predictors of breast cancer-specific and all-cause mortality. Data from three female US breast cancer survivor cohorts were harmonized in the After Breast Cancer Pooling Project (n = 9513). Delayed entry Cox proportional hazards models were used to examine the impact of three post-diagnosis lifestyle factors: body mass index (BMI), select comorbidities (diabetes only, hypertension only, or both), and very low physical activity (defined as physical activity <1.5 MET h/week) in individual models and together in multivariate models for breast cancer and all-cause mortality. For breast cancer mortality, the individual lifestyle models demonstrated a significant association with very low physical activity but not with the selected comorbidities or BMI. In the model that included all three lifestyle variables, very low physical activity was associated with a 22 % increased risk of breast cancer mortality (HR 1.22, 95 % CI 1.05, 1.42). For all-cause mortality, the three individual models demonstrated significant associations for all three lifestyle predictors. In the combined model, the strength and significance of the association of comorbidities (both hypertension and diabetes versus neither: HR 2.16, 95 % CI 1.79, 2.60) and very low physical activity (HR 1.35, 95 % CI 1.22, 1.51) remained unchanged, but the association with obesity was completely attenuated. These data indicate that after active treatment, very low physical activity, consistent with a sedentary lifestyle (and comorbidities for all-cause mortality), may account for the increased risk of mortality, with higher BMI, that is seen in other studies.

Lifestyle factors associated with cognitive functioning in breast cancer survivors.

OBJECTIVE: Weight, physical activity, and sleep are modifiable lifestyle factors that impact cognitive functioning in noncancer populations but have yet to be examined in cancer survivors. The aim of the study was to assess the relationship of obesity, physical activity, and sleep, with cognitive functioning among breast cancer survivors. METHODS: Participants were 136 early-stage postmenopausal breast cancer survivors who completed an assessment of neuropsychological testing, height, weight, physical activity, and sleep. Linear regression models examined the associations of the seven neuropsychological domains with obesity, physical activity, and sleep. Logistic regression models examined odd of impairment in each domain. All models controlled for breast cancer treatment variables and relevant demographic and clinical variables. RESULTS: Obese participants had significantly worse performance (ß = -5.04, standard error (SE) = 2.53) and were almost three times more likely to be impaired (odds ratio (OR) = 2.87; 95% CI: 1.02-8.10) on the Information processing domain. The highest tertile of physical activity was significantly related to better performance on the executive functioning domain (ß = 5.13, SE = 2.42) and attention domain (ß = 4.26, SE = 2.07). The middle tertile of physical activity was significantly related to better performance (ß = 9.00, SE = 3.09) and decreased odds of impairment (OR = 0.89, 95% CI: 0.07-0.91) on the visual-spatial domain. More hours of sleep per night was significantly associated with better performance (ß = 2.69, SE = 0.98) and decreased odds of impairment (OR = 0.52; 95% CI: 0.33-0.82) on the verbal functioning domain. CONCLUSIONS: These findings suggest that obesity, physical activity, and sleep are related to cognitive functioning among breast cancer survivors and have potential to be intervention targets to improve cognitive functioning.

Design and Rationale of Prolonged Nightly Fasting for Multiple Myeloma Prevention (PROFAST): Protocol for a Randomized Controlled Pilot Trial.

BACKGROUND: Obesity is an established, modifiable risk factor of multiple myeloma (MM); yet, no lifestyle interventions are routinely recommended for patients with overweight or obesity with MM precursor conditions. Prolonged nightly fasting is a simple, practical dietary regimen supported by research, suggesting that the synchronization of feeding-fasting timing with sleep-wake cycles favorably affects metabolic pathways implicated in MM. We describe the design and rationale of a randomized controlled pilot trial evaluating the efficacy of a regular, prolonged nighttime fasting schedule among individuals with overweight or obesity at high risk for developing MM or a related lymphoid malignancy. OBJECTIVE: We aim to investigate the effects of 4-month prolonged nightly fasting on body composition and tumor biomarkers among individuals with overweight or obesity with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or smoldering Waldenström macroglobulinemia (SWM). METHODS: Individuals with MGUS, SMM, or SWM aged ≥18 years and a BMI of ≥25 kg/m2 are randomized to either a 14-hour nighttime fasting intervention or a healthy lifestyle education control group. Participants' baseline diet and lifestyle patterns are characterized through two 24-hour dietary recalls: questionnaires querying demographic, comorbidity, lifestyle, and quality-of-life information; and wrist actigraphy measurements for 7 days. Fasting intervention participants are supported through one-on-one telephone counseling by a health coach and automated SMS text messaging to support fasting goals. Primary end points of body composition, including visceral and subcutaneous fat (by dual-energy x-ray absorptiometry); bone marrow adiposity (by bone marrow histology); and tumor biomarkers, specifically M-proteins and serum free light-chain concentrations (by gel-based and serum free light-chain assays), are assessed at baseline and after the 4-month study period; changes therein from baseline are evaluated using a repeated measures mixed-effects model that accounts for the correlation between baseline and follow-up measures and is generally robust to missing data. Feasibility is assessed as participant retention (percent dropout in each arm) and percentage of days participants achieved a ≥14-hour fast. RESULTS: The PROlonged nightly FASTing (PROFAST) study was funded in June 2022. Participant recruitment commenced in April 2023. As of July 2023, six participants consented to the study. The study is expected to be completed by April 2024, and data analysis and results are expected to be published in the first quarter of 2025. CONCLUSIONS: PROFAST serves as an important first step in exploring the premise that prolonged nightly fasting is a strategy to control obesity and obesity-related mechanisms of myelomagenesis. In evaluating the feasibility and impact of prolonged nightly fasting on body composition, bone marrow adipose tissue, and biomarkers of tumor burden, this pilot study may generate hypotheses regarding metabolic mechanisms underlying MM development and ultimately inform clinical and public health strategies for MM prevention. TRIAL REGISTRATION: ClinicalTrials.gov NCT05565638; http://clinicaltrials.gov/ct2/show/NCT05565638. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51368.

Mass spectrometry-detected MGUS is associated with obesity and other novel modifiable risk factors in a high-risk population.

ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition of multiple myeloma with few known risk factors. The emergence of mass spectrometry (MS) for the detection of MGUS has provided new opportunities to evaluate its risk factors. In total, 2628 individuals at elevated risk for multiple myeloma were enrolled in a screening study and completed an exposure survey (PROMISE trial). Participant samples were screened by MS, and monoclonal proteins (M-proteins) with concentrations of ≥0.2 g/L were categorized as MS-MGUS. Multivariable logistic models evaluated associations between exposures and MS outcomes. Compared with normal weight (body mass index [BMI] of 18.5 to <25 kg/m2), obesity (BMI of ≥30 kg/m2) was associated with MS-MGUS, adjusting for age, sex, Black race, education, and income (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.21-2.47; P = .003). High physical activity (≥73.5 metabolic equivalent of task (MET)-hours per week vs <10.5 MET-hours per week) had a decreased likelihood of MS-MGUS (OR, 0.45, 95% CI, 0.24-0.80; P = .009), whereas heavy smoking and short sleep had increased likelihood of MS-MGUS (>30 pack-years vs never smoker: OR, 2.19; 95% CI, 1.24-3.74; P = .005, and sleep <6 vs ≥6 hours per day: OR, 2.11; 95% CI, 1.26-3.42; P = .003). In the analysis of all MS-detected monoclonal gammopathies, which are inclusive of M-proteins with concentrations of <0.2 g/L, elevated BMI and smoking were associated with all MS-positive cases. Findings suggest MS-detected monoclonal gammopathies are associated with a broader range of modifiable risk factors than what has been previously identified. This trial was registered at www.clinicaltrials.gov as #NCT03689595.

Round Table Discussion on Optimal Clinical Trial Design in Precursor Multiple Myeloma.

SUMMARY: While the current approach to precursor hematologic conditions is to "watch and wait," this may change with the development of therapies that are safe and extend survival or delay the onset of symptomatic disease. The goal of future therapies in precursor hematologic conditions is to improve survival and prevent or delay the development of symptomatic disease while maximizing safety. Clinical trial considerations in this field include identifying an appropriate at-risk population, safety assessments, dose selection, primary and secondary trial endpoints including surrogate endpoints, control arms, and quality-of-life metrics, all of which may enable more precise benefit-risk assessment.

Targeting the fatty acid binding proteins disrupts multiple myeloma cell cycle progression and MYC signaling.

Multiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate. There is a critical need to find new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we identified and explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. In our work, myeloma cells were treated with FABP inhibitors (BMS3094013 and SBFI-26) and examined in vivo and in vitro for cell cycle state, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation properties. Myeloma cell responses to BMS309403, SBFI-26, or both, were also assessed with RNA sequencing (RNA-Seq) and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using the Cancer Dependency Map (DepMap). Finally, MM patient datasets (CoMMpass and GEO) were mined for FABP expression correlations with clinical outcomes. We found that myeloma cells treated with FABPi or with FABP5 knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation, increased apoptosis, and metabolic changes in vitro. FABPi had mixed results in vivo, in two pre-clinical MM mouse models, suggesting optimization of in vivo delivery, dosing, or type of FABP inhibitors will be needed before clinical applicability. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells in vitro. Clinical data demonstrated worse overall and progression-free survival in patients with high FABP5 expression in tumor cells. Overall, this study establishes the FABP family as a potentially new target in multiple myeloma. In MM cells, FABPs have a multitude of actions and cellular roles that result in the support of myeloma progression. Further research into the FABP family in MM is warrented, especially into the effective translation of targeting these in vivo.

Multiple myeloma is a type of blood cancer for which only a few treatments are available. Currently, only about half the patients with multiple myeloma survive for five years after diagnosis. Because obesity is a risk factor for multiple myeloma, researchers have been studying how fat cells or fatty acids affect multiple myeloma tumor cells to identify new treatment targets. Fatty acid binding proteins (FABPs) are one promising target. The FABPs shuttle fatty acids and help cells communicate. Previous studies linked FABPs to some types of cancer, including another blood cancer called leukemia, and cancers of the prostate and breast. A recent study showed that patients with multiple myeloma, who have high levels of FABP5 in their tumors, have worse outcomes than patients with lower levels. But, so far, no one has studied the effects of inhibiting FABPs in multiple myeloma tumor cells or animals with multiple myeloma. Farrell et al. show that blocking or eliminating FABPs kills myeloma tumor cells and slows their growth in a dish (in vitro) and in some laboratory mice. In the experiments, the researchers treated myeloma cells with drugs that inhibit FABPs or genetically engineered myeloma cells to lack FABPs. They also show that blocking FABPs reduces the activity of a protein called MYC, which promotes tumor cell survival in many types of cancer. It also changed the metabolism of the tumor cell. Finally, the team examined data collected from several sets of patients with multiple myeloma and found that patients with high FABP levels have more aggressive cancer. The experiments lay the groundwork for more studies to determine if drugs or other therapies targeting FABPs could treat multiple myeloma. More research is needed to determine why inhibiting FABPs worked in some mice with multiple myeloma but not others, and whether FABP inhibitors might work better if combined with other cancer therapies. There were no signs that the drugs were toxic in mice, but more studies must prove they are safe and effective before testing the drugs in humans with multiple myeloma. Designing better or more potent FABP-blocking drugs may also lead to better animal study results.

Personalised progression prediction in patients with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma (PANGEA): a retrospective, multicohort study.

BACKGROUND: Patients with precursors to multiple myeloma are dichotomised as having monoclonal gammopathy of undetermined significance or smouldering multiple myeloma on the basis of monoclonal protein concentrations or bone marrow plasma cell percentage. Current risk stratifications use laboratory measurements at diagnosis and do not incorporate time-varying biomarkers. Our goal was to develop a monoclonal gammopathy of undetermined significance and smouldering multiple myeloma stratification algorithm that utilised accessible, time-varying biomarkers to model risk of progression to multiple myeloma. METHODS: In this retrospective, multicohort study, we included patients who were 18 years or older with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma. We evaluated several modelling approaches for predicting disease progression to multiple myeloma using a training cohort (with patients at Dana-Farber Cancer Institute, Boston, MA, USA; annotated from Nov, 13, 2019, to April, 13, 2022). We created the PANGEA models, which used data on biomarkers (monoclonal protein concentration, free light chain ratio, age, creatinine concentration, and bone marrow plasma cell percentage) and haemoglobin trajectories from medical records to predict progression from precursor disease to multiple myeloma. The models were validated in two independent validation cohorts from National and Kapodistrian University of Athens (Athens, Greece; from Jan 26, 2020, to Feb 7, 2022; validation cohort 1), University College London (London, UK; from June 9, 2020, to April 10, 2022; validation cohort 1), and Registry of Monoclonal Gammopathies (Czech Republic, Czech Republic; Jan 5, 2004, to March 10, 2022; validation cohort 2). We compared the PANGEA models (with bone marrow [BM] data and without bone marrow [no BM] data) to current criteria (International Myeloma Working Group [IMWG] monoclonal gammopathy of undetermined significance and 20/2/20 smouldering multiple myeloma risk criteria). FINDINGS: We included 6441 patients, 4931 (77%) with monoclonal gammopathy of undetermined significance and 1510 (23%) with smouldering multiple myeloma. 3430 (53%) of 6441 participants were female. The PANGEA model (BM) improved prediction of progression from smouldering multiple myeloma to multiple myeloma compared with the 20/2/20 model, with a C-statistic increase from 0·533 (0·480-0·709) to 0·756 (0·629-0·785) at patient visit 1 to the clinic, 0·613 (0·504-0·704) to 0·720 (0·592-0·775) at visit 2, and 0·637 (0·386-0·841) to 0·756 (0·547-0·830) at visit three in validation cohort 1. The PANGEA model (no BM) improved prediction of smouldering multiple myeloma progression to multiple myeloma compared with the 20/2/20 model with a C-statistic increase from 0·534 (0·501-0·672) to 0·692 (0·614-0·736) at visit 1, 0·573 (0·518-0·647) to 0·693 (0·605-0·734) at visit 2, and 0·560 (0·497-0·645) to 0·692 (0·570-0·708) at visit 3 in validation cohort 1. The PANGEA models improved prediction of monoclonal gammopathy of undetermined significance progression to multiple myeloma compared with the IMWG rolling model at visit 1 in validation cohort 2, with C-statistics increases from 0·640 (0·518-0·718) to 0·729 (0·643-0·941) for the PANGEA model (BM) and 0·670 (0·523-0·729) to 0·879 (0·586-0·938) for the PANGEA model (no BM). INTERPRETATION: Use of the PANGEA models in clinical practice will allow patients with precursor disease to receive more accurate measures of their risk of progression to multiple myeloma, thus prompting for more appropriate treatment strategies. FUNDING: SU2C Dream Team and Cancer Research UK.

A comprehensive review of the impact of obesity on plasma cell disorders.

Multiple myeloma (MM) remains an incurable plasma cell malignancy. Although little is known about the etiology of MM, several metabolic risk factors such as obesity, diabetes, poor nutrition, many of which are modifiable, have been linked to the pathogenesis of numerous neoplasms including MM. In this article, we provide a detailed summary of what is known about the impact of obesity on the pathogenesis of MM, its influence on outcomes in MM patients, and discuss potential mechanisms through which obesity is postulated to influence MM risk and prognosis. Along with advancements in treatment modalities to improve survival in MM patients, focused efforts are needed to prevent or intercept MM at its earliest stages. The consolidated findings presented in this review highlight the need for clinical trials to assess if lifestyle modifications can reduce the incidence and improve outcomes of MM in high-risk populations. Data generated from such studies can help formulate evidence-based lifestyle recommendations for the prevention and control of MM.

Regular Aspirin Use and Mortality in Patients with Multiple Myeloma.

BACKGROUND: Inflammation is important in multiple myeloma pathogenesis, and regular aspirin use has been shown to confer a reduced risk of multiple myeloma. The influence of aspirin on survival after multiple myeloma diagnosis is unknown. METHODS: We identified 436 men and women diagnosed with multiple myeloma between 1980 and 2016 in the Health Professionals Follow-up Study and the Nurses' Health Study who reported aspirin intake biennially on follow-up questionnaires. Using multivariable Cox proportional hazards regression models, we estimated HRs and 95% confidence intervals (CI) associated with the effect of aspirin use on multiple myeloma-specific and overall mortality. RESULTS: Compared with nonusers, participants who used aspirin after diagnosis had a multivariable HR for multiple myeloma-specific mortality of 0.61 (95% CI, 0.46-0.79) and for overall mortality of 0.63 (95% CI, 0.49-0.80), after adjustment for age at diagnosis, year of diagnosis, sex, body mass index, prediagnosis aspirin use, and number of comorbidities. For postdiagnosis aspirin quantity, we observed a modest trend of reduction in multiple myeloma-specific and all-cause mortality with increasing number of 325-mg tablets of aspirin per week, although the CIs for 1 to <6 and ≥6 tablets overlapped. Results were not materially different before or after the availability of novel therapies (before vs. after the year 2000). Prediagnosis frequency or duration of aspirin use was not significantly associated with multiple myeloma-specific or overall mortality. CONCLUSIONS: These findings support the use of aspirin as a complementary strategy to enhance multiple myeloma survival. IMPACT: Confirmation in samples that have comprehensive clinical information is encouraged.