Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma (FiTNEss (UK-MRA Myeloma XIV Trial)): a study protocol for a randomised phase III trial.

INTRODUCTION: Multiple myeloma is a bone marrow cancer, which predominantly affects older people. The incidence is increasing in an ageing population.Over the last 10 years, patient outcomes have improved. However, this is less apparent in older, less fit patients, who are ineligible for stem cell transplant. Research is required in this patient group, taking into account frailty and aiming to improve: treatment tolerability, clinical outcomes and quality of life. METHODS AND ANALYSIS: Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma is a national, phase III, multicentre, randomised controlled trial comparing standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide to lenalidomide+ixazomib, in patients with newly diagnosed multiple myeloma not suitable for stem cell transplant. Overall, 740 participants will be registered into the trial to allow 720 and 478 to be randomised at induction and maintenance, respectively.All participants will receive IRD induction with the dosing strategy randomised (1:1) at trial entry. Patients randomised to the standard, reactive arm will commence at the full dose followed by toxicity dependent reactive modifications. Patients randomised to the adaptive arm will commence at a dose level determined by their International Myeloma Working Group frailty score. Following 12 cycles of induction treatment, participants alive and progression free will undergo a second (double-blind) randomisation on a 1:1 basis to maintenance treatment with lenalidomide+placebo versus lenalidomide+ixazomib until disease progression or intolerance. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the North East-Tyne & Wear South Research Ethics Committee (19/NE/0125) and capacity and capability confirmed by local research and development departments for each participating centre prior to opening to recruitment. Participants are required to provide written informed consent prior to trial registration. Trial results will be disseminated by conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN17973108, NCT03720041.

Minimal Residual Disease After Autologous Stem-Cell Transplant for Patients With Myeloma: Prognostic Significance and the Impact of Lenalidomide Maintenance and Molecular Risk.

PURPOSE: Minimal residual disease (MRD) can predict outcomes in patients with multiple myeloma, but limited data are available on the prognostic impact of MRD when assessed at serial time points in the context of maintenance therapy after autologous stem-cell transplant (ASCT) and the interaction between MRD and molecular risk. METHODS: Data from a large phase III trial (Myeloma XI) were examined to determine the relationship between MRD status, progression-free survival (PFS), and overall survival (OS) in post-ASCT patients randomly assigned to lenalidomide maintenance or no maintenance at 3 months after ASCT. MRD status was assessed by flow cytometry (median sensitivity 0.004%) before maintenance random assignment (ASCT + 3) and 6 months later (ASCT + 9). RESULTS: At ASCT + 3, 475 of 750 (63.3%) patients were MRD-negative and 275 (36.7%) were MRD-positive. MRD-negative status was associated with improved PFS (hazard ratio [HR] = 0.47; 95% CI, 0.37 to 0.58 P < .001) and OS (HR = 0.59; 95% CI, 0.40 to 0.85; P = .0046). At ASCT + 9, 214 of 326 (65.6%) were MRD-negative and 112 (34.4%) were MRD-positive. MRD-negative status was associated with improved PFS (HR = 0.20; 95% CI, 0.13 to 0.31; P < .0001) and OS (HR = 0.33; 95% CI, 0.15 to 0.75; P = .0077). The findings were very similar when restricted to patients with complete response/near complete response. Sustained MRD negativity from ASCT + 3 to ASCT + 9 or the conversion to MRD negativity by ASCT + 9 was associated with the longest PFS/OS. Patients randomly assigned to lenalidomide maintenance were more likely to convert from being MRD-positive before maintenance random assignment to MRD-negative 6 months later (lenalidomide 30%, observation 17%). High-risk molecular features had an adverse effect on PFS and OS even for those patients achieving MRD-negative status. On multivariable analysis of MRD status, maintenance therapy and molecular risk maintained prognostic impact at both ASCT + 3 and ASCT + 9. CONCLUSION: In patients with multiple myeloma, MRD status at both ASCT + 3 and ASCT + 9 is a powerful predictor of PFS and OS.

Experimental confirmation of a character-facing bias in literacy development.

When learning to write, children often mirror-reverse individual letters. For children learning to use the Latin alphabet, in a left-to-right writing culture, letters that appear to face left (such as J and Z) seem to be more prone to reversal than those that appear to face right (such as B and C). It has been proposed that, because most asymmetrical Latin letters face right, children statistically learn this general regularity and are subsequently biased to write any letter rightward. The evidence for this character-facing bias is circumstantial, however, because letter-facing direction is confounded with other factors that could affect error rates; for instance, J and Z are left-facing, but they are also infrequent. We report the first controlled experimental test of the character-facing bias. We taught 43 Scottish primary schoolchildren (aged 4.8-5.8 years) four artificial, letter-like characters, two of which were left-facing and two of which were right-facing. The characters were novel and so were not subject to prior exposure effects, and alternate groups of children were assigned to identical but mirror-reflected character sets. Children were three times more likely to mirror-write a novel character they had learned in a left-facing format than to mirror-write one they had learned in a right-facing format. This provides the first experimental confirmation of the character-facing bias in literacy development and suggests that implicit knowledge acquired from exposure to written language is readily generalized to novel letter-like forms.

Early life histories of the London poor using δ13C and δ15N stable isotope incremental dentine sampling.

High resolution incremental isotopic analysis of the dentine from early forming teeth, especially first molars (M1s), provides a means to assess the effects of poor childhood nutrition and healthcare on individuals in an assemblage where there are no infants to study. This approach is applied to an 18th and 19th century cemetery population associated with St Saviour's Almshouse burial ground in Southwark, London, to assess whether, or how, early dietary history, including weaning age, influenced health and nutritional status. The results show a general pattern in which non-breast milk foods were introduced before or by 6 months of age, as indicated by elevated δ(15) N during this period. Almost all individuals for which we also have second molar (M2) records, showed lower δ(15) N values from a very young age (>1 year) until approximately 8-10 years, compared to adult values. The overall results show a significant difference in δ(1) (3) C (p = 0 to 4sf, F = 17.327) and a weaker statistical difference in δ(15) N between males and females (p = 0.019, F = 5.581). One possible cause of this is a difference in the diet of males and females early in life, or alternatively, a greater susceptibility of males to nutritional deprivation compared to females. The latter argument is strengthened by a significant difference in the incidence of enamel hypoplasia between the males and females, with 7.7% of male teeth showing defects, compared to 3.9% of females.