Investigating Taste Perception of Maltodextrins Using Lactisole and Acarbose.

Previous research has demonstrated that complex carbohydrates (maltodextrins) can be perceived in the oral cavity. However, little research has been conducted to thoroughly investigate complex carbohydrate taste perception and contributing factors. This study explored the effects of the degree of polymerization and the concentration of complex carbohydrates on taste perception. Additionally, the impact of lactisole and acarbose on carbohydrate taste perception was investigated. Using a blinded, Latin Square design, participants (n = 40) received samples (control) or samples with acarbose (5 mM) or lactisole (1.4 mM). Per visit, participants received solutions: (1) short chain maltodextrin (average DP 6) (SCM), (2) long chain maltodextrin (average DP 24) (LCM), (3) maltose, and (4) glucose. Samples were evaluated in duplicate, both at low concentration and high concentration. Participants tasted the samples and rated sweetness, starchiness, and viscosity (mouthfeel) perceived on a 10 cm continuous line scale and perceived intensity on a Labelled Magnitude Scale. There was a significant effect of degree of polymerisation on sweetness (p = 0.001) and intensity (p = 0.001). For low concentration samples, no significant differences were found between LCM and acarbose LCM or SCM and acarbose SCM for sweetness, starchiness, or mouthfeel (all p > 0.05). Significant differences were observed between LCM and lactisole LCM for sweetness (1.1 ± 0.1 vs. 2.5 ± 0.3, p = 0.001), starchiness (1.4 ± 0.2 vs. 2.3 ± 0.3, p = 0.005), and mouthfeel (1.4 ± 0.2 vs. 2.3 ± 0.3, p = 0.013). In conclusion, the taste perception of maltodextrins is influenced by the degree of polymerisation. Furthermore, for this study, the sweet taste receptor was not involved in maltodextrin taste perception. While salivary α-amylase did not appear to influence taste perception with low concentration maltodextrins, further investigation is necessary.

Carbohydrate Oral Rinsing, Cycling Performance and Individual Complex Carbohydrate Taste Sensitivity.

The aim of this pilot study was to determine the effect of individual complex carbohydrate taste sensitivity on cycling performance with complex carbohydrate oral rinsing. Ten male participants completed five cycling time trials in a fasted state with a seven-day washout period between each trial. Participants completed a fixed amount of work (738.45 ± 150.74 kJ) as fast as possible on a cycle ergometer while rinsing with an oral rinse for 10 s every 12.5% of the trial. An oral rinse (maltodextrin, oligofructose, glucose, sucralose or water control) was given per visit in a randomised, crossover, blinded design. Afterwards, participants had their taste assessed with three stimuli, complex carbohydrate (maltodextrin), sweet (glucose) and sour (citric acid), using taste assessment protocol to determine individual taste sensitivity status. Participants were subsequently grouped according to their complex carbohydrate taste sensitivity and complex carbohydrate taste intensity. There were no significant effects of the oral rinses on cycling performance time (p = 0.173). Participants who did not have improvements in exercise performance with the maltodextrin rinse experienced a stronger taste intensity with complex carbohydrate stimuli at baseline (p = 0.047) and overall (p = 0.047) than those who did have improvements in performance. Overall, a carbohydrate oral rinse was ineffective in significantly improving cycling performance in comparison with a water control. However, when participants were grouped according to complex carbohydrate taste intensity, differences in exercise performance suggest that individual sensitivity status to complex carbohydrates could impact the efficacy of a carbohydrate-based oral rinse.

Taste but not smell sensitivities are linked to dietary macronutrient composition.

Macronutrient intake and composition of diets (i.e., carbohydrate, protein, and fat) can vary substantially across individuals. Chemosensory functions are hypothesised to play a key role in modulating nutrient choices and intake. The present study tests links between individual gustatory or olfactory supra-threshold sensitivities and dietary macronutrient intake. A total of 98 European males (N = 81 for final analyses; age: 20-40 yo; BMI: 18.9-48.1 kg∙m-2) were tested for supra-threshold sensitivities (d') to 3-gustatory (i.e., Sucrose, MSG, Dairy fat) and 3-olfactory stimuli (i.e., Vanillin, Methional, Maltol/Furaneol), followed by a 4-day weighed Food Record to give measures of macronutrient intake (kJ) and composition (%). With multivariate analyses (i.e., K-mean clustering, PCA, and Hierarchical Regression), gustatory and olfactory d' were compared across groups of individuals with distinct macronutrient composition or intake. Significant differences in gustatory d' were found across the clusters based on macronutrient composition (p < 0.05), but not for clusters based on intake. Hierarchical regressions suggested that gustatory d' played a significant role in predicting dietary carbohydrate composition and intake, with one-unit d' increase predicting reduction of 3%-4.66% (R2 = 0.21, F(5,75) = 5.38, p = 0.001). Moreover, every one-unit increase in d' to MSG increased protein composition by 3.45% (R2 = 0.10, F(5,75) = 2.83, p = 0.022) and intake by 392 kJ (R2 = 0.08, F(5,75) = 2.41, p = 0.044). By contrast, olfactory d' showed little association to macronutrient composition or intake (p > 0.05). Overall, we present intriguing new evidence that gustatory, but not olfactory, sensitivities are linked to dietary macronutrient composition, with relatively little effect on actual intake. These findings highlight possible action of a sensory-mediated mechanism guiding food choices.

Maltodextrin-Based Carbohydrate Oral Rinsing and Exercise Performance: Systematic Review and Meta-Analysis.

BACKGROUND: Carbohydrates are an important fuel for optimal exercise performance during moderate- and high-intensity exercise; however, carbohydrate ingestion during high-intensity exercise may cause gastrointestinal upset. A carbohydrate oral rinse is an alternative method to improve exercise performance in moderate- to high-intensity exercise with a duration of 30-75 min. This is the first systematic review and meta-analysis to comprehensively examine the isolated effect of maltodextrin-based rinsing on exercise performance. OBJECTIVE: The objective of this review was to establish the effect of a maltodextrin-based carbohydrate oral rinse on exercise performance across various modes of exercise. Furthermore, a secondary objective was to determine the effects of moderators [(1) participant characteristics; (2) oral rinse protocols; (3) exercise protocol (i.e. cycling, running etc.) and (4) fasting] on exercise performance while using a maltodextrin-based, carbohydrate oral rinse. METHODS: Five databases (MEDLINE, PsycINFO, Embase, SPORTDiscus and Global Health) were systematically searched for articles up to March 2021 and screened using Covidence (a systematic review management tool). A random effects robust meta-analysis and subgroup analyses were performed using Stata Statistical Software: Release 16. RESULTS: Thirty-five articles met the inclusion criteria and were included in the systematic review; 34 of these articles were included in the meta-analysis. When using a conventional meta-analytic approach, overall, a carbohydrate oral rinse improved exercise performance in comparison with a placebo (SMD = 0.15, 95% CI 0.04, 0.27; p = 0.01). Furthermore, when implementing an adjusted, conservative, random effects meta-regression model using robust variance estimation, overall, compared with placebo, a carbohydrate oral rinse demonstrated evidence of improving exercise performance with a small effect size (SMD = 0.17, 95% CI - 0.01, 0.34; p = 0.051). CONCLUSION: This systematic review and meta-analysis demonstrates that a maltodextrin-based carbohydrate oral rinse can improve exercise performance. When comparing the two meta-analytic approaches, although non-significant, the more robust, adjusted, random effects meta-regression model demonstrated some evidence of a maltodextrin-based carbohydrate oral rinse improving exercise performance overall.

Consumer Acceptance of Brown and White Rice Varieties.

Rice is consumed as a staple food by more than half of the world's population. Due to a higher fibre and micronutrient content, brown rice is more nutritious than white rice, but the consumption of brown rice is significantly lower than that of white rice, primarily due to sensory attributes. Therefore, the present research aimed to identify the sensory attributes which drive liking of Australian-grown brown and white rice varieties. Participants (n = 139) tasted and scored (9-point hedonic scale) their liking (i.e., overall liking, aroma, colour and texture) of brown and white rice types of Jasmine (Kyeema), Low GI (Doongara), and Medium grain rice (Amaroo). In addition, participants scored aroma, colour, hardness, fluffiness, stickiness, and chewiness, on Just About Right Scales. A within-subjects crossover design with randomised order (William's Latin Square design) was used with six repeated samples for liking and Just About Right scales. Penalty analyses were applied to determine the relative influence of perception of sensory attributes on consumer liking of the rice varieties. Across all varieties, white rice was liked more than brown rice due to the texture and colour, and Jasmine rice was preferred over Low GI and Medium Grain. Rice texture (hardness and chewiness) was the most important sensory attribute among all rice varieties and aroma was important for driving of liking between white rice varieties.

The role of an individual's olfactory discriminability in influencing snacking and habitual energy intake.

Recent studies have revealed close links between human olfaction, appetite, and food choice. However, it remains unclear whether olfactory sensitivity plays a direct role in determining food and energy intake. The present study addresses this question by assessing relationships between individual olfactory discriminability (at a suprathreshold level), snacking, and habitual energy intake. A total of 92 healthy Caucasian males (mean age = 26.1, SD = 5.8) were tested for their olfactory discriminability (measured by d') to three food-related odorants (O1 - Vanillin, O2 - Methional, and O3 - Maltol/Furaneol mixture) with a 2-AFC method of constant stimuli. These sensory data were then analysed with two separate measures of food consumption - (1) snack energy intake within an ad libitum buffet setting; (2) habitual energy intake using four-day weighed food records. Univariate analyses of variance revealed significant results with regards to O1. Specifically, individuals with higher discriminability consumed significantly less energy from snacking as opposed to their less sensitive counterparts (p = 0.05). However, no significant relationship was found between individual olfactory discriminability and habitual energy intake. While recent years have seen increasing research focus on how external olfactory cues affect food consumption, our study offers particularly novel insights regarding the role of individual olfactory sensitivity in shaping eating behaviour.

Associations between sweet taste function, oral complex carbohydrate sensitivity, liking and consumption of ad libitum sweet and non-sweet carbohydrate milkshakes among female adults.

Excess energy intake is recognised as a strong contributing factor to the global rise of being overweight and obese. The aim of this paper was to investigate if oral sensitivity to complex carbohydrate relates to ad libitum consumption of complex carbohydrate foods in a sample group of female adults. Participants' ((n 51 females): age 23·0 (sd 0·6) years (range 20·0-41·0 years); excluding restrained eaters) sensitivity towards maltodextrin (oral complex carbohydrate) and glucose (sweet taste) was assessed by measuring detection threshold (DT) and suprathreshold intensity perception (ST). A crossover design was used to assess consumption of two different iso-energetic preload milkshakes and ad libitum milkshakes - (1) glucose-based milkshake, (2) maltodextrin-based milkshake. Ad libitum intake (primary outcome) and eating rate, liking, hunger, fullness and prospective consumption ratings were measured. Participants who were more sensitive towards complex carbohydrate (maltodextrin DT) consumed significantly more maltodextrin-based milkshake in comparison with less-sensitive participants (P = 0·01) and this was independent of liking. Participants who had higher liking for glucose-based milkshake consumed significantly more glucose-based milkshake in comparison with participants with lower hedonic ratings (P = 0·049). The results provide support regarding the role of the oral system sensitivity (potentially taste) to complex carbohydrate and the prospective to overconsume complex carbohydrate-based milkshake in a single sitting.

Sugar reduction without compromising sensory perception. An impossible dream?

Sugar reduction is a major technical challenge for the food industry to address in response to public health concerns regarding the amount of added sugars in foods. This paper reviews sweet taste perception, sensory methods to evaluate sugar reduction and the merits of different techniques available to reduce sugar content. The use of sugar substitutes (non-nutritive sweeteners, sugar alcohols, and fibres) can achieve the greatest magnitude of sugar and energy reduction, however bitter side tastes and varying temporal sweet profiles are common issues. The use of multisensory integration principles (particularly aroma) can be an effective approach to reduce sugar content, however the magnitude of sugar reduction is small. Innovation in food structure (modifying the sucrose distribution, serum release and fracture mechanics) offers a new way to reduce sugar without significant changes in food composition, however may be difficult to implement in food produced on a large scale. Gradual sugar reduction presents difficulties for food companies from a sales perspective if acceptability is compromised. Ultimately, a holistic approach where food manufacturers integrate a range of these techniques is likely to provide the best progress. However, substantial reduction of sugar in processed foods without compromising sensory properties may be an impossible dream.

The Associations Between Oral Complex Carbohydrate Sensitivity, BMI, Liking, and Consumption of Complex Carbohydrate Based Foods.

Recent work suggests that humans may perceive complex carbohydrates and that their sensitivity to simple carbohydrates (i.e., glucose and sucrose) is independent from tasting complex carbohydrates. The aim of this study was to confirm whether humans could sense complex carbohydrates from a range of concentration levels; and if their oral sensitivity to complex carbohydrate relates to their BMI, liking, and consumption of complex carbohydrate-based foods using a large sample group of adults. Participants' (n = 92 females, age 23.7 ± 0.5 yr [range, 19 to 47 yr]) oral sensitivity towards complex carbohydrate (maltodextrin) and sweet taste function (glucose) was assessed by measuring detection threshold and suprathreshold intensity perception (gLMS). Participants were asked to complete an online version of a Food Frequency Questionnaire and a Likes and Dislikes Questionnaire. Hedonic ratings for complex carbohydrate and sweet solutions, as well as for a range of complex carbohydrate and sweet prototypical foods, were also measured. Consistent with previous findings, there was large interindividual variation in detection and intensity measures for maltodextrin and glucose. No significant associations were found between oral complex carbohydrate sensitivity, Body Mass Index (BMI), and frequency of consumption of complex carbohydrate-based foods measured. Similarly, no differences were observed between liking of complex carbohydrates, BMI, and food intake. All in, these results from a large sample group further support the proposition that complex carbohydrates are not invisible to the human palate, and can be sensed in the oral cavity even at low concentration levels.

Physical activity-equivalent label reduces consumption of discretionary snack foods.

OBJECTIVE: The present research aimed to investigate the impact of the physical activity calorie equivalent (PACE) front-of-pack label on consumption, prospective consumption and liking of familiar and unfamiliar discretionary snack foods. DESIGN: In a within-subject randomised design, participants tasted and rated liking (9-point hedonic scale) and prospective consumption (9-point category scale) of four different snack foods with four different labels (i.e. blank, fake, PACE, PACE doubled) and four control snack foods. The twenty snack foods were presented during two 45 min sessions (i.e. ten snack foods per session) which were separated by one week. The amount participants sampled of each snack food was measured. SETTING: The study was conducted in the Centre for Advanced Sensory Sciences laboratory at Deakin University, Australia. SUBJECTS: The participants were 153 university students (126 females, twenty-seven males, mean age 24·3 (sd 4·9) years) currently enrolled in an undergraduate nutrition degree at Deakin University. RESULTS: When the PACE label was present on familiar snack foods, participants sampled 9·9 % (22·8 (sem 1·4) v. 25·3 (sem 1·5) g, P=0·03) less than when such label was not present. This was in line with a decreased prospective snack food consumption of 9·1 % (3·0 (sem 0·2) v. 3·3 (sem 0·2) servings, P=0·03). Such pattern was not seen in unfamiliar snacks. CONCLUSIONS: The PACE label appears to be a promising way to decrease familiar discretionary snack food consumption in young, health-minded participants.

Pomalidomide-dexamethasone in refractory multiple myeloma: long-term follow-up of a multi-cohort phase II clinical trial.

Despite therapeutic advances, multiple myeloma remains incurable, with limited options for patients with refractory disease. We conducted a large, multi-cohort clinical trial testing various doses and treatment schedules of pomalidomide and dexamethasone (Pom/dex) in patients with refractory multiple myeloma. Overall, 345 patients were enrolled to six cohorts based on number and type of prior lines of therapy, pomalidomide dose and schedule. Median prior lines of therapy were three with near universal prior exposure to proteasome inhibitors and/or immunomodulatory drugs. A confirmed response rate of 35% was noted for all cohorts (range 23-65%) with higher responses in cohorts with fewer prior lines of therapy. Median time to confirmed response was ⩽2 months and the longest progression-free survival and overall survival seen in any cohort were 13.1 and 47.9 months, respectively. Observed adverse reactions were as expected, with myelosuppression and fatigue being the most common hematologic and non-hematologic adverse events (AEs), respectively. Longer durations of treatment and response, higher response rates and fewer AEs were noted with the 2 mg pomalidomide dose. This is the longest follow-up data for Pom/dex in refractory multiple myeloma and will help shape the real-world utilization of this regimen.

Clinical presentation and outcomes in light chain amyloidosis patients with non-evaluable serum free light chains.

Hematologic response criteria in light chain (AL) amyloidosis require the difference in involved and uninvolved free light chains (dFLC) to be at least 5 mg/dl. We describe the clinical presentation and outcomes of newly diagnosed amyloidosis patients with dFLC <5 mg/dl (non-evaluable dFLC; 14%, n=165) compared with patients with dFLC ⩾5 mg/dl (evaluable dFLC; 86%, n=975). Patients with non-evaluable dFLC had less cardiac involvement (40% vs 80%, P<0.001), less liver involvement (11% vs 17%, P=0.04) and a trend toward less gastrointestinal involvement (18% vs 25%, P=0.08). However, significantly higher renal involvement (72% vs 56%, P=0.0002) was observed in the non-evaluable dFLC cohort. Differences in treatment patterns were observed, with 51% of treated patients undergoing upfront stem cell transplantation in the non-evaluable cohort compared with 28% in the evaluable dFLC group (P<0.001). Progression-free survival (61 vs 13 months, P<0.001) and overall survival (OS; 101 vs 29 months, P<0.001) were significantly longer in the non-evaluable dFLC cohort. Normalization of involved light chain levels and decrease in dFLC <1 mg/dl (baseline at least 2 mg/dl) were predictive of OS and associated with better dialysis-free survival and may be used for response assessment in patients with non-evaluable FLC levels.

Natural history of t(11;14) multiple myeloma.

Translocation (11;14) on interphase fluorescent in situ hybridization in plasma cells is regarded as a standard risk prognostic marker in multiple myeloma based on studies conducted before introduction of current therapies. We identified 365 patients with t(11;14), and 730 matched controls:132 patients with non-(11;14) translocations and 598 patients with no chromosomal translocation. The median progression-free survival for the three groups were 23.0 (95% confidence interval (CI), 20.8-27.6), 19.0 (95% CI, 15.8-22.7) and 28.3 (95% CI, 25.7-30.6) months, respectively (P<0.01). The median overall survival (OS) for t(11;14), non-(11;14) translocation and no-translocation groups were 74.4 (95% CI, 64.8-89.3), 49.8 (95% CI, 40.0-60.6) and 103.6 (95% CI, 85.2-112.3) months, respectively (P<0.01). Excluding those with 17p abnormality, the median OS in the three groups were 81.7 (95% CI, 67.0-90.7), 58.2 (95% CI, 47.0-76.4) and 108.3 (95% CI, 92.4-140.1) months, respectively (P<0.01). The above relationship held true in patients with age <65 years, international staging system (ISS) I/II stage or those who received novel agent-based induction. Advanced age (hazard ratio (HR): 1.98), 17p abnormality (HR: 2.2) and ISS III stage (HR: 1.59) at diagnosis predicted reduced OS in patients with t(11;14). These results suggest that outcomes of t(11;14) MM are inferior to other standard risk patients.

Evidence supporting oral sensitivity to complex carbohydrates independent of sweet taste sensitivity in humans.

Compared to simple sugars, complex carbohydrates have been assumed invisible to taste. However, two recent studies proposed that there may be a perceivable taste quality elicited by complex carbohydrates independent of sweet taste. There is precedent with behavioural studies demonstrating that rats are very attracted to complex carbohydrates, and that complex carbohydrates are preferred to simple sugars at low concentrations. This suggests that rats may have independent taste sensors for simple sugars and complex carbohydrates. The aim of this paper is to investigate oral sensitivities of two different classes of complex carbohydrates (a soluble digestible and a soluble non-digestible complex carbohydrate), and to compare these to other caloric and non-nutritive sweeteners in addition to the prototypical tastes using two commonly used psychophysical measures. There were strong correlations between the detection thresholds and mean intensity ratings for complex carbohydrates (maltodextrin, oligofructose) (r = 0.94, P < 0.001). There were no significant correlations between the detection thresholds of the complex carbohydrates (maltodextrin, oligofructose) and the sweeteners (glucose, fructose, sucralose, Rebaudioside A, erythritol) (all P > 0.05). However, moderate correlations were observed between perceived intensities of complex carbohydrates and sweeteners (r = 0.48-0.61, P < 0.05). These data provide evidence that complex carbohydrates can be sensed in the oral cavity over a range of concentrations independent of sweet taste sensitivity at low concentrations, but with partial overlap with sweet taste intensity at higher concentrations.

Salivary leptin and TAS1R2/TAS1R3 polymorphisms are related to sweet taste sensitivity and carbohydrate intake from a buffet meal in healthy young adults.

The influence of sweet taste sensitivity on food intake is not well understood. We investigated the involvement of salivary leptin and SNP of the sweet taste receptor genes (TAS1R2/TAS1R3) on sweet taste sensitivity, sensory-specific satiety (SSS) and macronutrient intake in healthy human adults. In all, nineteen high sweet sensitivity (HS) and eleven low sweet sensitivity (LS) subjects were classified based on the sweetness perception of one solution (9 mm sucrose) forced-choice triangle test. All participants completed a randomised crossover design experiment where they consumed one of three iso-energetic soup preloads differing in primary taste quality (sweet, non-sweet taste-control or no-taste energy-control). A period of 1 h after the preload, participants were offered a buffet meal consisting of foods varying in taste (sweet or non-sweet) and fat content. Subjective measures included hunger/fullness and SSS for sweetness. Saliva and buccal cells were collected to measure leptin level and to study the TAS1R2/TAS1R3 specific SNP, respectively. Salivary leptin concentrations were significantly higher in LS than HS participants (P<0·05). In addition, HS showed stronger sweet SSS compared with LH participants (P<0·05), and consumed less carbohydrate (% energy) and more non-sweet foods than LS (P<0·01 and P<0·05, respectively). Alleles from each TAS1R2 locus (GG compared with AA alleles of rs12033832, and CT/CC compared with TT alleles of rs35874116) were related to higher consumption of carbohydrates (% energy) and higher amount of sweet foods, respectively (P<0·05). In contrast, no associations were found for the TAS1R3 alleles. These results contribute to understand the links between taste sensitivity, macronutrient appetite and food consumption.

PIWIs, piRNAs and Retrotransposons: Complex battles during reprogramming in gametes and early embryos.

Gamete and embryo development are indispensable processes for successful reproduction. Cells involved in these processes acquire pluripotency, the ability to differentiate into multiple different cell types, through a series of events known as reprogramming that lead to profound changes in histone and DNA methylation. While essential for pluripotency, this epigenetic remodelling removes constraints that normally limit the expression of genomic sequences known as transposable elements (TEs). Unconstrained TE expression can lead to many deleterious consequences including infertility, so organisms have evolved complex and potent mechanistic arsenals to target and suppress TE expression during reprogramming. This review will focus on the control of transposable elements in gametes and embryos, and one important TE suppressing system known as the PIWI pathway. This broadly conserved, small RNA-targeted silencing mechanism appears critical for fertility in many species and may participate in multiple aspects of gene regulation in reproduction and other contexts.

Prognostic implications of abnormalities of chromosome 13 and the presence of multiple cytogenetic high-risk abnormalities in newly diagnosed multiple myeloma.

Fluorescence in situ hybridization evaluation is essential for initial risk stratification in multiple myeloma. While the presence of specific cytogenetic high-risk abnormalities (HRA) is known to confer a poor prognosis, less is known about the cumulative effect of multiple HRA. We studied 1181 patients with newly diagnosed multiple myeloma who received novel agents as first-line therapy. High-risk abnormalities were defined as t(4;14), t(14;16), t(14;20) and del(17p). There were 884 patients (75%) without any HRA and 297 patients (25%) with HRA, including 262 (22%) with one HRA and 35 (3%) with two HRA. The presence of one HRA (versus zero, hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.32-2.05, p<0.001) and the presence of two HRA (versus zero, HR 3.15, 95% CI 2.00-4.96, p<0.001) were of prognostic significance after adjusting for other prognostic factors. Abnormalities of chromosome 13 were of prognostic significance independent of the established HRA: Monosomy 13 (HR 1.27, 95% CI 1.04-1.56, P=0.022) and del(13q) (HR 0.48, 95% CI 0.28-0.81, P=0.006) with opposite effects. Patients with HRA experienced worse overall survival suggesting a cumulative adverse effect of multiple HRA. Abnormalities of chromosome 13 were of prognostic significance after adjusting for other prognostic factors.

High somatic mutation and neoantigen burden are correlated with decreased progression-free survival in multiple myeloma.

Tumor-specific mutations can result in immunogenic neoantigens, both of which have been correlated with responsiveness to immune checkpoint inhibitors in highly mutagenic cancers. However, early results of single-agent checkpoint inhibitors in multiple myeloma (MM) have been underwhelming. Therefore, we sought to understand the relationship between mutation and neoantigen landscape of MM patients and responsiveness to therapies. Somatic mutation burden, neoantigen load, and response to therapy were determined using interim data from the MMRF CoMMpass study (NCT01454297) on 664 MM patients. In this population, the mean somatic and missense mutation loads were 405.84(s=608.55) and 63.90(s=95.88) mutations per patient, respectively. There was a positive linear relationship between mutation and neoantigen burdens (R2=0.862). The average predicted neoantigen load was 23.52(s=52.14) neoantigens with an average of 9.40(s=26.97) expressed neoantigens. Survival analysis revealed significantly shorter progression-free survival (PFS) in patients with greater than average somatic missense mutation load (N=163, 0.493 vs 0.726 2-year PFS, P=0.0023) and predicted expressed neoantigen load (N=214, 0.555 vs 0.729 2-year PFS, P=0.0028). This pattern is maintained when stratified by disease stage and cytogenetic abnormalities. Therefore, high mutation and neoantigen load are clinically relevant risk factors that negatively impact survival of MM patients under current standards of care.

Changes in uninvolved immunoglobulins during induction therapy for newly diagnosed multiple myeloma.

Little is known about the impact of multiple myeloma (MM) treatment on uninvolved immunoglobulins (Ig). We identified 448 patients who received high-dose dexamethasone (HD-DEX), lenalidomide and dexamethasone (RD), bortezomib and dexamethasone (VD), bortezomib, cyclophosphamide and dexamethasone (VCD) or bortezomib, lenalidomide and dexamethasone (VRD) for newly diagnosed MM at our institution between 2000 and 2013, and who had available data on absolute lymphocyte count (ALC) and quantitative uninvolved Ig at baseline and at the end of four cycles of therapy. Changes in ALC and uninvolved Ig were significantly different across treatments, with VCD and HD-DEX producing reductions in uninvolved Ig, and RD, VD and VRD leading to increases in uninvolved Ig. In addition, treatment with RD, VD and VRD was independently associated with higher odds of achieving a ⩾25% increase in or normalization of the primary uninvolved Ig on multivariate analysis. Although achievement of a humoral response in the primary uninvolved Ig was associated with a higher odds of achieving VGPR or better after four cycles of therapy, it was not associated with improved overall survival. These data highlight the different mechanisms of action of MM drugs and point toward a possible role for the use of VCD in treating antibody-mediated autoimmune disease.

Phase I trial of systemic administration of Edmonston strain of measles virus genetically engineered to express the sodium iodide symporter in patients with recurrent or refractory multiple myeloma.

MV-NIS is an Edmonston lineage oncolytic measles virus expressing the human sodium iodide symporter-a means for monitoring by non-invasive imaging of radioiodine. Patients with relapsed, refractory myeloma who had explored all other treatment options were eligible for this Phase I trial. Cohort 1 was treated with intravenous MV-NIS, and Cohort 2 received cyclophosphamide 2 days prior to MV-NIS. Thirty-two patients were treated. Cohort 1 initially enrolled to four dose levels without reaching maximum tolerated dose (MTD) and subsequently to two higher dose levels when improved virus manufacture technology made it possible. MTD was not reached in Cohort 1, and TCID50 1011 is the dose being used in a Phase II trial of single agent MV-NIS. Grade 3-4 adverse events in both cohorts at all dose levels were: neutropenia (n=9); leukocyte count decreased (n=5); thrombocytopenia (n=2); and CD4 lymphocytes decreased, anemia and lymphopenia (each n=1). MV-N RNA sequences were amplified from gargle specimens, blood and urine. 123I scans were positive in eight patients. One patient achieved a complete response; transient drops in serum free light chains were seen in other patients. MV-NIS is capable of replicating before being cleared by the immune system. Oncolytic viruses offer a promising new modality for the targeted infection and destruction of disseminated myeloma.