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.

Context-specific tolerance to the ataxic effects of alcohol.

Tolerance to alcohol and many other drugs can become conditioned to specific contextual cues present at the time of drug administration. Context-specific tolerance occurs to a variety of alcohol's effects, including changes in hormone levels, body temperature and locomotor activity. The present study investigated whether context-specific tolerance can occur to the ataxic effects of alcohol. Baseline levels of motor coordination were assessed using a tilting plane apparatus. During a 7-day tolerance acquisition phase, subjects received an injection of either alcohol (1.5 g/kg i.p.) or saline (15 ml/kg i.p.) in a novel testing room and were then placed in the tilting plane apparatus for a period of 20 min. Approximately 5 h after the first injection, subjects received a second injection in the colony room and were then placed in their home cages. One group of subjects, the paired group, received alcohol in the testing room and saline in the colony room. An unpaired group received saline in the testing room and alcohol in the colony room. A no alcohol control group received saline in both environments. Following the tolerance acquisition phase, all subjects were injected with alcohol (1.5 g/kg i.p.) and tested for ataxia in the tilting plane apparatus. Subjects in the paired group were less ataxic than subjects in the control group during all four testing blocks following alcohol administration. In contrast, subjects in the unpaired group were less ataxic than the control subjects only during the 15-min testing block. Relative to baseline scores, the paired group exhibited deficits only during the 5- and 10-min testing blocks, while subjects in the unpaired and control groups exhibited deficits during all four testing blocks. These data strongly suggest that tolerance to the ataxic effects of alcohol can become conditioned to contextual cues present at the time of alcohol administration.

Differential effects of ethanol on motor coordination in adolescent and adult rats.

Recent evidence suggests that adolescence represents a unique period of sensitivity to the effects of ethanol. Adolescent animals are more sensitive than adults to many of the effects of ethanol, including ethanol-induced learning and memory impairments, while being less sensitive to others, including ethanol-induced sedation. It is well known that ethanol produces dramatic impairments in balance and motor coordination. While previous research suggests that adolescents and adults do not differ in their sensitivity to the effects of relatively low doses of ethanol on motor coordination, it is not known whether differences in performance would emerge at higher doses. The present study compared the impact of a range of ethanol doses (1.0, 2.0 and 3.0 g/kg) on motor coordination in adolescent [postnatal day (PD) 35-40] and adult (PD 70-75) rats. Motor coordination was assessed using the tilting plane test before ethanol administration (baseline) and at 15, 30, 60, 120 and 180 min after ethanol administration. Performance was not affected by 1.0 g/kg ethanol in either age group. However, adults were more impaired than adolescents at nearly every time point following administration of both 2.0 and 3.0 g/kg ethanol. The results provide further evidence that adolescents and adults are differentially sensitive to the behavioral effects of ethanol. Given the critical role of motor coordination in the ability to operate motor vehicles and the central role of balance and coordination in field sobriety tests, these data could have important implications if extended to human subjects.