The effects of short-term, progressive exercise training on disease activity in smouldering multiple myeloma and monoclonal gammopathy of undetermined significance:a single-arm pilot study

Background: High levels of physical activity are associated with reduced risk of the blood cancer multiple myeloma (MM). MM is preceded by the asymptomatic stages of monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) which are clinically managed by watchful waiting. A case study (N = 1) of a former elite athlete aged 44 years previously indicated that a multi-modal exercise programme reversed SMM disease activity. To build from this prior case study, the present pilot study firstly examined if short-term exercise training was feasible and safe for a group of MGUS and SMM patients, and secondly investigated the effects on MGUS/SMM disease activity. Methods: In this single-arm pilot study, N = 20 participants diagnosed with MGUS or SMM were allocated to receive a 16-week progressive exercise programme. Primary outcome measures were feasibility and safety. Secondary outcomes were pre- to post-exercise training changes to blood biomarkers of MGUS and SMM disease activity– monoclonal (M)-protein and free light chains (FLC)– plus cardiorespiratory and functional fitness, body composition, quality of life, blood immunophenotype, and blood biomarkers of inflammation. Results: Fifteen (3 MGUS and 12 SMM) participants completed the exercise programme. Adherence was 91 ± 11%. Compliance was 75 ± 25% overall, with a notable decline in compliance at intensities > 70% V̇O2PEAK. There were no serious adverse events. There were no changes to M-protein (0.0 ± 1.0 g/L, P =.903), involved FLC (+ 1.8 ± 16.8 mg/L, P =.839), or FLC difference (+ 0.2 ± 15.6 mg/L, P =.946) from pre- to post-exercise training. There were pre- to post-exercise training improvements to diastolic blood pressure (− 3 ± 5 mmHg, P =.033), sit-to-stand test performance (+ 5 ± 5 repetitions, P =.002), and energy/fatigue scores (+ 10 ± 15%, P =.026). Other secondary outcomes were unchanged. Conclusions: A 16-week progressive exercise programme was feasible and safe, but did not reverse MGUS/SMM disease activity, contrasting a prior case study showing that five years of exercise training reversed SMM in a 44-year-old former athlete. Longer exercise interventions should be explored in a group of MGUS/SMM patients, with measurements of disease biomarkers, along with rates of disease progression (i.e., MGUS/SMM to MM). Registration: https://www.isrctn.com/ISRCTN65527208 (14/05/2018)

AIM (Artery in microgravity): Design and development of an ice cubes mission

The Artery In Microgravity (AIM) project is the first experiment to be selected for the “Orbit Your Thesis!” programme of ESA Academy. It is a 2U experiment cube designed for the ICE Cubes facility on board of the International Space Station. The experiment is expected to be launched on SpaceX-20 in early 2020. The project is being developed by an international group of students from ISAE-SUPAERO and Politecnico di Torino, under the supervision of the ISAE-SUPAERO and Politecnico di Torino staff. The experiment is a test-bench for investigating haemodynamics in microgravity focusing on coronary heart disease, the most common form of cardiovascular disease and the cause of approximately 9 million deaths every year. Coronary heart disease is caused by stenosis of the coronary artery due to the build-up of plaque. While the development of atherosclerosis is not fully understood, the primary event seems to be subtle and repeated injury to the artery walls through various mechanisms including physical stresses from flow disturbances as well as from systemic and biological risk factors. In the presence of severe stenosis, patients are treated with the implantation of one or more coronary stents, which are tubular scaffolds devoted to restore and maintain myocardial perfusion. The coronary stenting procedure is largely applied (e.g., 1.8 million stents per year implanted in USA) In view of the impact that coronary artery disease has on humans, as well as of the increasing number of people that will be involved in space flights in the future, the way astronauts in space coronary hemodynamics is affected by the absence of gravity in the presence of stenosis or of stenting needs to be investigated in depth. In addition, as most stents are metallic objects, the radiation exposure in space might interact with their surface, altering blood flow, inducing particles release and ultimately leading to stent failure. Therefore, the aim of AIM is to start studying the vascular haemodynamics in a stented and a stenosed coronary artery on Earth and in microgravity and the stent-radiation coupling. This will allow to learn about the effect gravity plays on coronary artery haemodynamics, the effects of microgravity and radiation on the performance of implantable devices and ultimately the risks of myocardial infarction to astronauts on long-distance spaceflight. The experimental setup consists of a closed hydraulic loop containing two models of a coronary artery in series. An electric pump and reservoir will control the flow of a blood-mimicking fluid through the system. One model of the coronary artery will contain a coronary stent. The pressure of the fluid will be studied along its path using a series of pressure sensors and a camera will visualise the flow. The same experiments will be repeated on the ground with the same conditions as the in-flight model for comparison. The paper will outline in detail the design and development of the AIM experiment cube and the results of testing. The full data and results will be available after the completion of the mission which is expected to be between March and June 2020

Immune response to COVID-19 vaccination is attenuated by poor disease control and antimyeloma therapy with vaccine driven divergent T cell response

Myeloma patients frequently respond poorly to bacterial and viral vaccination. A few studies have reported poor humoral immune responses in myeloma patients to COVID-19 vaccination. Using a prospective study of myeloma patients in UK Rudy Study cohort, we assessed humoral and Interferon gamma release assay (IGRA) cellular immune responses to COVID-19 vaccination post second COVID-19 vaccine administration. We report data from 214 adults with myeloma (n=204) or smouldering myeloma (n=10) who provided blood samples at least 3 weeks after second vaccine dose. Positive Anti-Spike antibody levels (> 50 IU/ml) were detected in 189/203 (92.7%), positive IGRA responses were seen in 97/158 (61.4%) myeloma patients. Only 10/158 (6.3%) patients were identified to have both a negative IGRA and negative Anti-Spike protein antibody response. 95/158 (60.1%) patients produced positive results for both anti-Spike protein serology and IGRA. After adjusting for disease severity and myeloma therapy, poor humoral immune response was predicted by male gender. Predictors of poor IGRA included anti-CD38/ anti-BCMA therapy and Pfizer-BioNTech (PB) vaccination. Further work is required to understand the clinical significance of divergent cellular response to vaccination

Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate

Background: We and others have identified the aldo-keto reductase AKR1C3 as a potential drug target in prostate cancer, breast cancer and leukaemia. As a consequence, significant effort is being invested in the development of AKR1C3-selective inhibitors. Methods: We report the screening of an in-house drug library to identify known drugs that selectively inhibit AKR1C3 over the closely related isoforms AKR1C1, 1C2 and 1C4. This screen initially identified tetracycline as a potential AKR1C3-selective inhibitor. However, mass spectrometry and nuclear magnetic resonance studies identified that the active agent was a novel breakdown product (4-methyl(de-dimethylamine)-tetracycline (4-MDDT)). Results: We demonstrate that, although 4-MDDT enters AML cells and inhibits their AKR1C3 activity, it does not recapitulate the anti-leukaemic actions of the pan-AKR1C inhibitor medroxyprogesterone acetate (MPA). Screens of the NCI diversity set and an independently curated small-molecule library identified several additional AKR1C3-selective inhibitors, none of which had the expected anti-leukaemic activity. However, a pan AKR1C, also identified in the NCI diversity set faithfully recapitulated the actions of MPA. Conclusions: In summary, we have identified a novel tetracycline-derived product that provides an excellent lead structure with proven drug-like qualities for the development of AKR1C3 inhibitors. However, our findings suggest that, at least in leukaemia, selective inhibition of AKR1C3 is insufficient to elicit an anticancer effect and that multiple AKR1C inhibition may be required

Determinants of durable humoral and T cell immunity in myeloma patients following <scp>COVID</scp>‐19 vaccination

Objective To describe determinants of persisting humoral and cellular immune response to the second COVID-19 vaccination among patients with myeloma. Methods This is a prospective, observational study utilising the RUDYstudy.org platform. Participants reported their second and third COVID-19 vaccination dates. Myeloma patients had an Anti-S antibody level sample taken at least 21 days after their second vaccination and a repeat sample before their third vaccination. Results 60 patients provided samples at least 3 weeks (median 57.5 days) after their second vaccination and before their third vaccination (median 176.0 days after second vaccine dose). Low Anti-S antibody levels (<50 IU/mL) doubled during this interval (p = .023) and, in the 47 participants with T-spot data, there was a 25% increase negative T-spot tests (p = .008). Low anti–S antibody levels prior to the third vaccination were predicted by lower Anti-S antibody level and negative T-spot status after the second vaccine. Independent determinants of a negative T-spot included increasing age, previous COVID infection, high CD4 count and lower percentage change in Anti-S antibody levels. Conclusions Negative T-spot results predict low Anti-S antibody levels (<50 IU/mL) following a second COVID-19 vaccination and a number of biomarkers predict T cell responses in myeloma patients

Active multiple myeloma suppresses and typically eliminates coexisting MGUS

Background: Myeloma is consistently preceded by premalignant monoclonal gammopathy of undetermined significance (MGUS). In >5% of MGUS patients there is a second MGUS clone (biclonal gammopathy of undetermined significance; BGUS), yet, at myeloma diagnosis, presentation of biclonal gammopathy myeloma (BGMy) is considered less frequent, implying that myeloma eradicates coexisting MGUS. Methods: In the largest study of its kind, we assessed BGMy frequency amongst 6399 newly diagnosed myeloma patients enrolled in recent UK clinical trials. Results: Compared to expected prevalence (i.e., >5% of MGUS have BGUS), only 58 of 6399 (0.91%) newly diagnosed myeloma patients had BGMy, indicating myeloma typically eliminates coexistent MGUS. In these 58 BGMy cases, the MGUS plasma cell clone was greatly suppressed in size compared to typical levels observed in conventional MGUS; contrarily, the MGUS clone did not inhibit the myeloma plasma cell clone in BGMy. Conclusion: Myeloma eliminates the majority of competing MGUS, and when it does not, the MGUS clone is substantially reduced in size