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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]

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]

Background: Myeloma causes profound immunodeficiency and recurrent, serious infections. Around 5500 new cases of myeloma are diagnosed per year in the UK, and a quarter of patients will have a serious infection within 3 months of diagnosis. We aimed to assess whether patients newly diagnosed with myeloma benefit from antibiotic prophylaxis to prevent infection, and to investigate the effect on antibiotic-resistant organism carriage and health care-associated infections in patients with newly diagnosed myeloma.Methods: TEAMM was a prospective, multicentre, double-blind, placebo-controlled randomised trial in patients aged 21 years and older with newly diagnosed myeloma in 93 UK hospitals. All enrolled patients were within 14 days of starting active myeloma treatment. We randomly assigned patients (1:1) to levofloxacin or placebo with a computerised minimisation algorithm. Allocation was stratified by centre, estimated glomerular filtration rate, and intention to proceed to high-dose chemotherapy with autologous stem cell transplantation. All investigators, patients, laboratory, and trial co-ordination staff were masked to the treatment allocation. Patients were given 500 mg of levofloxacin (two 250 mg tablets), orally once daily for 12 weeks, or placebo tablets (two tablets, orally once daily for 12 weeks), with dose reduction according to estimated glomerular filtration rate every 4 weeks. Follow-up visits occurred every 4 weeks up to week 16, and at 1 year. The primary outcome was time to first febrile episode or death from all causes within the first 12 weeks of trial treatment. All randomised patients were included in an intention-to-treat analysis of the primary endpoint. This study is registered with the ISRCTN registry, number ISRCTN51731976, and the EU Clinical Trials Register, number 2011-000366-35.Findings: Between Aug 15, 2012, and April 29, 2016, we enrolled and randomly assigned 977 patients to receive levofloxacin prophylaxis (489 patients) or placebo (488 patients). Median follow-up was 12 months (IQR 8-13). 95 (19%) first febrile episodes or deaths occurred in 489 patients in the levofloxacin group versus 134 (27%) in 488 patients in the placebo group (hazard ratio 0·66, 95% CI 0·51-0·86; p=0·0018. 597 serious adverse events were reported up to 16 weeks from the start of trial treatment (308 [52%] of which were in the levofloxacin group and 289 [48%] of which were in the placebo group). Serious adverse events were similar between the two groups except for five episodes (1%) of mostly reversible tendonitis in the levofloxacin group.Interpretation: Addition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths compared with placebo without increasing health care-associated infections. These results suggest that prophylactic levofloxacin could be used for patients with newly diagnosed myeloma undergoing anti-myeloma therapy.Funding: UK National Institute for Health Research. [ABSTRACT FROM AUTHOR]

In November 2014 the International Myeloma Working Group ( IMWG) revised the definition of multiple myeloma, such that asymptomatic patients with newly diagnosed multiple myeloma without any of the traditional ' CRAB' (hyper calcaemia, renal impairment, anaemia, bone disease) end organ damage criteria but with one of three new criteria would be recommended to start treatment. Previously, the standard of care for such patients was expectant management. These three new criteria are: greater than 60% clonal plasma cells on bone marrow biopsy, a serum free light chain ( sFLC) ratio of >100 (the involved sFLC must be >100 mg/l) and greater than one unequivocal focal lesion on advanced imaging (low dose whole body computerized tomography, magnetic resonance imaging, 18F fluorodeoxyglucose positron emission tomography). Although this would appear to affect a small number of patients, the impact of these changes are broad, leading to an increased use of advanced imaging, a debate around the management of patients previously diagnosed with smouldering myeloma, changed terminology and clinical trial design and an extension of the use of biomarkers. For the first time the philosophy of treatment in myeloma will change from treatment initiation only being triggered by overt end organ damage to an era where sub clinical risk factors will also be taken into account. [ABSTRACT FROM AUTHOR]

The article discusses poor performance status (PS) in elderly patients with aggressive B cell lymphomas can benefit from intensive chemotherapy. It states that some predictors of toxicity enable toxicity to be avoided in a dying patient, but data are sparse regarding intensively treated aggressive B cell lymphoma in elderly patients with very poor PS.

A letter to the editor regarding the dose-related side effects of thalidomide in the treatment of myeloma is presented.

The article discusses the possible role of lenalidomide to control gastrointestinal bleeding in hereditary haemorrhagic telangiectasia (HHT). HHT is an inherited disorder of abnormal blood vessel formation and causes mucous membrane bleeding that progresses in severity with age. With the side effects of thalidomide, a better tolerated drug lenalidomide is being considered as an alternative, focusing on a patient, whose life-threatening bleeding was controlled by it.

The article presents the authors' views on the implications of ultra low dose thalidomide on elderly patients with myeloma. They commented that the improvement in performance status in the responders concurs with emerging data that a response to therapy and diminution in disease bulk improves the quality of life of patients with myeloma. They added that the intake of 25 milligrams of thalidomide may enable patients to continue maintenance treatment longer compared with conventional dose.

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]

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]

The article presents two case studies related to multiple myeloma. It mentions that a 75-year-old female has complained of headaches, confusion and fluctuating drowsiness, and neutrophils and platelet count of female were normal after examine with magnetic resonance imaging and cerebral computed tomography. It also mentions a 79-year-old male with immunoglobulin M myeloma was admitted with cough and fever, and states that he was diagnosed with human cryptococcal infection.

A letter to the editor is presented in response to the previously published article about therapy-related myelodysplasia.

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]

Examines the contribution of the humoral response to HIV-1 at seroconversion to the disease outcome after 84hours in the United States. Availability of the software to the public with hemophilia; Implications of the Kaplan-Meier survival analysis; Progression of HIV related disease complex.

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]

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]

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]

A growing population of long-term survivors of myeloma is now accumulating the 'late effects' not only of myeloma itself, but also of several lines of treatment given throughout the course of the disease. It is thus important to recognise the cumulative burden of the disease and treatment-related toxicity in both the stable and active phases of myeloma, some of which is unlikely to be detected by routine monitoring. We summarise here the evidence for the key late effects in long-term survivors of myeloma, including physical and psychosocial consequences (in Parts 1 and 2 respectively), and recommend the use of late-effects screening protocols in detection and intervention. The early recognition of late effects and effective management strategies should lead to an improvement in the management of myeloma patients, although evidence in this area is currently limited and further research is warranted. [ABSTRACT FROM AUTHOR]

Abnormalities of the p53 gene are known to confer detrimental effects in chronic lymphocytic leukaemia (CLL) and are associated with short survival. We have used high dose methylprednisolone (HDMP) to treat 25 patients with advanced refractory CLL of whom 45% had p53 abnormalities shown by one or more methods: flow cytometry, fluorescent in situ hybridisation and direct DNA sequencing. Fifteen were resistant to fludarabine and 16 were non-responders to their most recent therapy. Methylprednisolone had a cytotoxic effect on lymphocytes from 95% of cases assessed by an ex vivo apoptotic drug sensitivity index (DSI). HDMP was given alone or in combination with other drugs: vincristine, CCNU, Ara-C, doxorubicin, mitoxantrone and chlorambucil, according to the results of DSI. Three patients were treated twice and each treatment was analysed separately. The overall response rate was 77% with a median duration of 12 months (range 7 –23+). Responders included 5/10 with abnormal p53, of which two achieved nodular PR. Patients with p53 abnormalities fared worse than those with normal p53. There were no differences in response according to whether HDMP was used alone or in combination. Nine of the 22 evaluable patients (3 NR and 6 PR) have died from progressive disease or transformation. Main toxicity was infection in 7/25 patients. Event free and overall survival were significantly better in responders vs non-responders (P>0.0001 and P=0.04 respectively). Patients with a DSI of 100% to steroids had a better overall and event free survival, but this was not statistically significant. This study demonstrates that HDMP alone or in combination with other agents is a useful treatment strategy in refractory CLL including patients with p53 abnormalities. [ABSTRACT FROM AUTHOR]