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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. [ABSTRACT FROM AUTHOR]

Introduction: Late presentation of multiple myeloma (MM) heightens the risk of complication risks, including end-organ damage. This study aimed to: 1) detail the diagnostic journey of MM patients, encompassing symptoms, initial diagnoses, and healthcare professionals met; 2) establish the median duration from symptom onset to MM diagnosis; and 3) examine factors linked to timely MM diagnosis within 12 weeks. Methods: A total of 300 adults self-reporting MM were analysed from the Rare and Undiagnosed Diseases cohort Study (RUDY). The RUDY study is a web-based platform, where participants provide dynamic consent and self-report their MM diagnosis and information about their diagnostic journey. This includes the estimated date of initial potential first symptoms, descriptions of these symptoms, the healthcare professionals they consulted, and other diagnoses received before the MM diagnosis. Descriptive statistics, combinatorial analyses and logistic regression analyses were used to describe and examine the diagnostic journey of individuals with MM. Results: Overall, 52% of the participants reported other diagnoses before MM diagnosis, with musculoskeletal disorders (47.8%), such as osteoporosis, costochondritis, or muscle strains, being the most common. The most prevalent initial reported symptom was back pain/vertebral fractures (47%), followed by chest/shoulder pain, including rib pain and fractures (20%), and fatigue/tiredness (19.7%). 40% of participants were diagnosed by direct referral from primary care to haematology without seeing other healthcare professionals whilst 60% consulted additional specialists before diagnosis. The median time from symptom onset to MM diagnosis was 4 months (IQR 2-10 months, range 0-172). Seeing an Allied Healthcare Professional such as a physiotherapist, chiropractor or an osteopath (OR = 0.25, 95% CI [0.12, 0.47], p <0.001), experiencing infection symptoms (OR = 0.32, 95% CI [0.13, 0.76], p = 0.013), and having chest or shoulder pain (OR = 0.45, 95% CI [0.23, 0.86], p = 0.020) were associated with a lower likelihood of being diagnosed with MM within 12 weeks. Older age (OR = 1.04, 95% CI [1.02, 1.07], p = 0.001) was associated with a higher likelihood of diagnosis within 12 weeks. Discussion: Developing resources for allied health professionals may improve early recognition of MM. [ABSTRACT FROM AUTHOR]

Simple Summary: Myeloma, a blood cancer, is rare and hard to diagnose. People often suffer irreversible organ damage by the time of diagnosis. Myeloma is preceded by a premalignant phase that is easily identifiable on a blood test. Currently, there is no screening for this, because most people do not progress to myeloma. We aimed to inform guidelines and screening by refining our understanding of how patients developing myeloma describe their symptoms and how those symptoms relate to organ damage. We found that patients rarely describe 'bone pain' but simply 'pain'. Low-impact crush fractures of the backbones appear to be under-recognised as abnormal. At least 30% of patients have irreversible organ damage at diagnosis. People who developed myeloma fared better if they had previously been diagnosed to have the premalignant condition. Screening based on certain symptoms, possibly combined with imaging and laboratory results, may speed up the diagnosis of myeloma. Multiple myeloma (MM) patients risk diagnostic delays and irreversible organ damage. In those with newly diagnosed myeloma, we explored the presenting symptoms to identify early signals of MM and their relationships to organ damage. The symptoms were recorded in patients' own words at diagnosis and included diagnostic time intervals. Those seen by a haematologist >6 months prior to MM diagnosis were classified as precursor disease (PD). Most (962/977) patients provided data. Back pain (38%), other pain (31%) and systemic symptoms (28%) predominated. Patients rarely complain of 'bone pain', simply 'pain'. Vertebral fractures are under-recognised as pathological and are the predominant irreversible organ damage (27% of patients), impacting the performance status (PS) and associated with back pain (odds ratio (OR) 6.14 [CI 4.47–8.44]), bone disease (OR 3.71 [CI 1.88–7.32]) and age >65 years (OR 1.58 [CI 1.15–2.17]). Renal failure is less frequent and associated with gastrointestinal symptoms (OR 2.23 [CI1.28–3.91]), age >65 years (OR 2.14 [CI1.28–3.91]) and absence of back pain (OR 0.44 [CI 0.29–0.67]). Patients with known PD (n = 149) had fewer vertebral fractures (p = 0.001), fewer adverse features (p = 0.001), less decline in PS (p = 0.001) and a lower stage (p = 0.04) than 813 with de novo MM. Our data suggest subgroups suitable for trials of 'symptom-directed' screening: those with back pain, unexplained pain, a general decline in health or low-impact vertebral compression fractures. [ABSTRACT FROM AUTHOR]

Infection risk is high in healthcare workers working with COVID-19 patients but the risk in non-COVID clinical environments is less clear. We measured infection rates early in the pandemic by SARS-CoV-2 antibody and/or a positive PCR test in 1118 HCWs within various hospital environments with particular focus on non-COVID clinical areas. Infection risk on non-COVID wards was estimated through the surrogate metric of numbers of patients transferred from a non-COVID to a COVID ward. Staff infection rates increased with likelihood of COVID exposure and suggested high risk in non-COVID clinical areas (non patient-facing 23.2% versus patient-facing in either non-COVID environments 31.5% or COVID wards 44%). High numbers of patients admitted to COVID wards had initially been admitted to designated non-COVID wards (22–48% at peak). Infection risk was high during a pandemic in all clinical environments and non-COVID designation may provide false reassurance. Our findings support the need for common personal protective equipment standards in all clinical areas, irrespective of COVID/non-COVID designation. [ABSTRACT FROM AUTHOR]

Summary: 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 the 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 three 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. In all, 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 (B‐cell maturation antigen) therapy and Pfizer‐BioNTech vaccination. Further work is required to understand the clinical significance of divergent cellular response to vaccination. [ABSTRACT FROM AUTHOR]

All patients who had had a previous infection had a robust antibody response to the first dose of COVID-19 vaccine and 60% of patients had an optimal immune response to the first dose of COVID-19 vaccination. COVID symptoms, testing, shielding impact on patient-reported outcomes and early vaccine responses in individuals with multiple myeloma Keywords: myeloma; COVID-19; vaccination; wellbeing; shielding EN myeloma COVID-19 vaccination wellbeing shielding 95 98 4 12/27/21 20220101 NES 220101 Patients with myeloma have been shielded and self-isolated since the start of the COVID-19 pandemic, due to the concern for and subsequent reports of higher risk of severe COVID-19 disease and mortality.1 In addition, guidelines have encouraged attenuation of myeloma therapeutics or a switch to oral therapies, ostensibly to reduce hospital foot-fall, facilitate shielding and potentially to limit further treatment-related immune suppression.2 Myeloma requires ongoing immune-suppressive chemotherapy, frequent medical visits and has previously demonstrated universally poor response to vaccinations.3 The protective titre of antibodies required to prevent re-infection is unclear, as is the ability to protect patients from SARS-CoV-2 virus variants of concern (VoC). [Extracted from the article]

Summary: Multiple myeloma is associated with significant early morbidity and mortality, with considerable end organ damage often present at diagnosis. The Tackling EArly Morbidity and Mortality in Multiple Myeloma (TEAMM) trial was used to evaluate routes to diagnosis in patients with myeloma and the relationship between diagnostic pathways, time to diagnosis and disease severity. A total of 915 participants were included in the study. Fifty‐one per cent were diagnosed by direct referral from primary care to haematology; 29% were diagnosed via acute services and 20% were referred via other secondary care specialties. Patients diagnosed via other secondary care specialties had a longer diagnostic interval (median 120 days vs. 59 days) without an increase in features of severe disease, suggesting they had a relatively indolent disease. Marked intrahospital delay suggests possible scope for improvement. A quarter of those diagnosed through acute services reported >30 days from initial hospital consultation to haematology assessment. Participants diagnosed through acute services had poorer performance status (P < 0·0001) and higher burden of end organ damage (P < 0·0001) with no difference in the overall length of diagnostic pathway compared to those diagnosed by direct referral (median 59 days). This suggests that advanced disease in patients presenting through acute services predominantly reflects disease aggression. [ABSTRACT FROM AUTHOR]

Objective: Myeloma is primarily a disease of the elderly, but older patients experience poorer outcomes. Effective treatments may not be offered to older patients over fears about toxicity, particularly for those with comorbidities. We aimed to characterise the trend in survival disparity between older and younger patients and assess to what extent comorbidity might explain these disparities. Methods: We examined records for 56 010 patients diagnosed with myeloma in England between 1998‐2014. The Hospital Episode Statistics database provided information on comorbidity. Net survival was estimated for each diagnosis period. Adjusted excess hazard ratios for the effect of age were estimated using flexible parametric models. Results: Net survival increased for all age groups over the study period. However, older patients experienced a higher risk of death from their disease consistent between 1998 and 2014. Adjusting for comorbidity made little difference to the estimates. Conclusion: Factors other than comorbidity must explain the poorer survival experience of elderly patients. Treatment data were not examined and should be employed by future population studies. Inconsistent treatment of elderly patients with myeloma may be prevented by further use of pragmatic clinical trials which are inclusive of older adults, and also wider utilisation of frailty scores. [ABSTRACT FROM AUTHOR]

The treatment of relapsed aggressive lymphoma remains a challenge. Platinum-containing chemotherapy is standard of care. Gemcitabine/oxaliplatin (Gem-Ox) with or without rituximab (R) is an outpatient regimen with a favorable toxicity profile. This retrospective ‘real world’ study reports outcomes for 44 unselected patients with relapsed/refractory aggressive lymphoma treated with Gem-Ox ± R. 41% had primary refractory disease. The overall response rate (ORR) was 43% with a complete response (CR) of 30%. Response to the prior treatment regimen significantly affected the ORR with only 8% achieving CR if prior remission was <12 months. Grade 3–4 hematological toxicity was common and 22% had febrile neutropenia. Eight patients proceeded to stem cell transplant. Overall, outcomes remain poor with a median overall survival of 8 months. In this high-risk group of patients, Gem-Ox ± R results in similar responses to other more toxic, inpatient regimens and should therefore be considered as second line therapy in relapsed lymphoma. [ABSTRACT FROM AUTHOR]

Seven cases of thromboembolism were found amongst 23 patients treated with thalidomide for myeloma over a total of 141.5 patient treatment months. Five thromboembolic events were venous (two severe) and two arterial. A historical control of 18 similar patients not given thalidomide had one thromboembolism over 289 months. We found no underlying thrombophilic tendency in the affected patients. We suggest that the thalidomide may predispose to thromboembolism at even lower doses than previously reported (mean dose 150 mg). The two most severe thromboses occurred on 100 mg thalidomide alone, not associated with chemotherapy or glucocorticoids. We raise the possibility that arterial thromboembolism may also occur in association with thalidomide. Some patients continued thalidomide after the event, together with warfarin, with no further thromboembolism. [ABSTRACT FROM AUTHOR]

Background: The adjuvanted recombinant zoster vaccine (Shingrix) can prevent herpes zoster in older adults and autologous haemopoietic stem cell transplant recipients. We evaluated the safety and immunogenicity of this vaccine in adults with haematological malignancies receiving immunosuppressive cancer treatments.Methods: In this phase 3, randomised, observer-blind, placebo-controlled study, done at 77 centres worldwide, we randomly assigned (1:1) patients with haematological malignancies aged 18 years and older to receive two doses of the adjuvanted recombinant zoster vaccine or placebo 1-2 months apart during or after immunosuppressive cancer treatments, and stratified participants according to their underlying diseases. The co-primary objectives of the study were the evaluation of safety and reactogenicity of the adjuvanted recombinant zoster vaccine compared with placebo from the first vaccination up to 30 days after last vaccination in all participants; evaluation of the proportion of participants with a vaccine response in terms of anti-glycoprotein E humoral immune response to the adjuvanted recombinant zoster vaccine at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia; and evaluation of the anti-glycoprotein E humoral immune responses to the vaccine compared with placebo at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. We assessed immunogenicity in the per-protocol cohort for immunogenicity and safety in the total vaccinated cohort. The study is registered with ClinicalTrials.gov, number NCT01767467, and with the EU Clinical Trials Register, number 2012-003438-18.Findings: Between March 1, 2013, and Sept 10, 2015, we randomly assigned 286 participants to adjuvanted recombinant zoster vaccine and 283 to placebo. 283 in the vaccine group and 279 in the placebo group were vaccinated. At month 2, 119 (80·4%, 95% CI 73·1-86·5) of 148 participants had a humoral vaccine response to adjuvanted recombinant zoster vaccine, compared with one (0·8%, 0·0-4·2) of 130 participants in the placebo group, and the adjusted geometric mean anti-glycoprotein E antibody concentration was 23 132·9 mIU/mL (95% CI 16 642·8-32 153·9) in the vaccine group and 777·6 mIU/mL (702·8-860·3) in the placebo group (adjusted geometric mean ratio 29·75, 21·09-41·96; p<0·0001) in all patients, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. Humoral and cell-mediated immune responses persisted above baseline until month 13 in all strata and, as expected, vaccine was more reactogenic than placebo (within 7 days after vaccination pain was reported by 221 [79·5%] of 278 vaccine group participants and 45 [16·4%] of 274 placebo group participants; fatigue was reported by 162 [58·3%] of 278 vaccine group participants and 102 [37·2%] of 274 placebo group participants). Incidences of unsolicited or serious adverse events, potential immune-mediated diseases, disease-related events, and fatal serious adverse events were similar between the groups.Interpretation: The immunocompromised adult population with haematological malignancies is at high risk for herpes zoster. The adjuvanted recombinant zoster vaccine, which is currently licensed in certain countries for adults aged 50 years and older, is likely to benefit this population.Funding: GlaxoSmithKline Biologicals SA. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Competing interests: ABC, K-LR, DAC, AH, CO, RH and PB report grants and non-financial support from BMS/Celgene, grants and non-financial support from Merck Sharpe & Dohme, grants and non-financial support from Amgen, grants and non-financial support from Takeda, during the conduct of the trial. DAC also reports travel support from Celgene Corporation. CPawlyn reports receiving honoraria and/or travel support from Amgen, BMS/Celgene, Janssen, Sanofi and Takeda. MK consultancy: AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm, Seattle Genetics, Takeda; honoraria: BMS/Celgene, Janssen, Takeda; Research funding: BMS/Celgene; Travel/educational support: BMS/Celgene, Janssen, Takeda. SB reports receiving research funding from Takeda. KB—Advisory Boards Janssen: BMS/Celgene, Takeda, Novartis. Speaker Honoraria: Janssen, BMS/Celgene, Sanofi, Takeda. Support to attend educational meetings: Janssen, BMS/Celgene, Takeda, GSK. GJ reports research funding from Takeda, Onyx, MSD & BMS/Celgene with consultancy from Janssen, Takeda, Sanofi, Oncopeptides, Karyopharm, Pfizer, Roche & BMS/Celgene. GC reports research funding from Janssen, Takeda, Amgen & BMS/Celgene with consultancy from Janssen, Takeda, Sanofi, Oncopeptides, Karyopharm, Pfizer, Roche & BMS/Celgene. MD reports Stock held in Abingdon Health. JB, RdT, NR, JJ, CParrish, HG, DM, BD, RO, MJ and BK have no declared competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Myeloma causes profound immunodeficiency and recurrent serious infections. There are approximately 5500 new UK cases of myeloma per annum, and one-quarter of patients will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection. However, the use of prophylaxis has not been established in myeloma and may be associated with health-care-associated infections (HCAIs), such as Clostridium difficile . There is a need to assess the benefits and cost-effectiveness of the use of antibacterial prophylaxis against any risks in a double-blind, placebo-controlled, randomised clinical trial., Objectives: To assess the risks, benefits and cost-effectiveness of prophylactic levofloxacin in newly diagnosed symptomatic myeloma patients., Design: Multicentre, randomised, double-blind, placebo-controlled trial. A central telephone randomisation service used a minimisation computer algorithm to allocate treatments in a 1 : 1 ratio., Setting: A total of 93 NHS hospitals throughout England, Northern Ireland and Wales., Participants: A total of 977 patients with newly diagnosed symptomatic myeloma., Intervention: Patients were randomised to receive levofloxacin or placebo tablets for 12 weeks at the start of antimyeloma treatment. Treatment allocation was blinded and balanced by centre, estimated glomerular filtration rate and intention to give high-dose chemotherapy with autologous stem cell transplantation. Follow-up was at 4-week intervals up to 16 weeks, with a further follow-up at 1 year., Main Outcome Measures: The primary outcome was to assess the number of febrile episodes (or deaths) in the first 12 weeks from randomisation. Secondary outcomes included number of deaths and infection-related deaths, days in hospital, carriage and invasive infections, response to antimyeloma treatment and its relation to infection, quality of life and overall survival within the first 12 weeks and beyond., Results: In total, 977 patients were randomised (levofloxacin, n  = 489; placebo, n  = 488). A total of 134 (27%) events (febrile episodes, n  = 119; deaths, n  = 15) occurred in the placebo arm and 95 (19%) events (febrile episodes, n  = 91; deaths, n  = 4) occurred in the levofloxacin arm; the hazard ratio for time to first event (febrile episode or death) within the first 12 weeks was 0.66 (95% confidence interval 0.51 to 0.86; p  = 0.002). Levofloxacin also reduced other infections (144 infections from 116 patients) compared with placebo (179 infections from 133 patients; p -trend of 0.06). There was no difference in new acquisitions of C. difficile , methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase Gram-negative organisms when assessed up to 16 weeks. Levofloxacin produced slightly higher quality-adjusted life-year gains over 16 weeks, but had associated higher costs for health resource use. With a median follow-up of 52 weeks, there was no significant difference in overall survival ( p  = 0.94)., Limitations: Short duration of prophylactic antibiotics and cost-effectiveness., Conclusions: During the 12 weeks from new diagnosis, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced febrile episodes and deaths without increasing HCAIs or carriage. Future work should aim to establish the optimal duration of antibiotic prophylaxis and should involve the laboratory investigation of immunity, inflammation and disease activity on stored samples funded by the TEAMM (Tackling Early Morbidity and Mortality in Myeloma) National Institute for Health Research Efficacy and Mechanism Evaluation grant (reference number 14/24/04)., Trial Registration: Current Controlled Trials ISRCTN51731976., Funding Details: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 62. See the NIHR Journals Library website for further project information., Competing Interests: Mark T Drayson reports personal fees from Abingdon Health (Abingdon Health, York, UK) outside the submitted work. Stella Bowcock reports personal fees from Amgen (Amgen, CA, USA) and Celgene (Celgene, NJ, USA) outside the submitted work, non-financial support to attend educational meetings and has a patent issued for a device broadly related to the work. Tim Planche reports personal fees from Pfizer (Pfizer, CT, USA), Actellion (Actellion, Allschnil, Switzerland) and Astellas (Astellas Pharma, Tokyo, Japan) outside the submitted work. Kwee Yong reports grants from Janssen (Janssen Pharmaceutica, Beerse, Belgium), Celgene and Chugai (Chugai Pharmaceutical Co Tokyo, Japan) outside the submitted work. David Meads is a member of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) European Economic and Social Committee (EESC) Methods Group and the NIHR HTA EESC Panel. Claire T Hulme is a member of the NIHR HTA Commissioning Board. Janet A Dunn is a member of the NIHR Efficacy and Mechanism Evaluation board.