This guideline provides consensus opinion on the investigations required for people presenting with suspected monoclonal gammopathy of renal significance to both nephrology and haematology physicians. The guideline discusses the principles of treating a patient with MGRS and provides recommendations for both supportive management and haematological therapy. It details the recommended on-going monitoring required for both specialty areas.

The precise link between inflammation and pathogenesis of myelodysplastic syndrome (MDS) is yet to be fully established. We developed a novel method to measure ASC/NLRP3 protein specks which are specific for the NLRP3 inflammasome only. We combined this with cytokine profiling to characterise various inflammatory markers in a large cohort of patients with lower risk MDS in comparison to healthy controls and patients with defined autoinflammatory disorders (AIDs). The ASC/NLRP3 specks were significantly elevated in MDS patients compared to healthy controls (p < 0.001) and these levels were comparable to those found in patients with AIDs. The distribution of protein specks positive only for ASC was different to ASC/NLRP3 ones suggesting that other ASC-containing inflammasome complexes might be important in the pathogenesis of MDS. Patients with MDS-SLD had the lowest levels of interleukin (IL)-1β, tumour necrosis factor (TNF), IL-23, IL-33, interferon (IFN) γ and IFN-α2, compared to other diagnostic categories. We also found that inflammatory cytokine TNF was positively associated with MDS progression to a more aggressive form of disease and IL-6 and IL-1β with time to first red blood cell transfusion. Our study shows that there is value in analysing inflammatory biomarkers in MDS, but their diagnostic and prognostic utility is yet to be fully validated.

Background Arising in blood and lymph-forming tissues, haematological malignancies (leukaemias, lymphomas and myelomas) are the fifth most common group of cancers. Around 60% are currently incurable and follow a chronic, remitting–relapsing pathway often initially managed by ‘watch & wait’. This involves hospital-based monitoring, followed by treatment if the cancer progresses (which not all do) and then further observation, in a process that may continually repeat. New treatments are constantly emerging, survival is improving and prevalence is rising, but population-based data documenting entire care pathway are sparse. Hence, empirically-based incidence and prevalence estimates about various treatment states (watch and wait, first-line treatment, observation, second-line treatment, etc.) and patterns of healthcare activity are lacking. Likewise, despite complex trajectories, anxiety-provoking watch and wait, and therapies that impede quality of life and incur marked healthcare costs, evidence about patient preferences for information sharing and treatment decisions is scant. Objectives Primary – to generate high-quality, evidence-based information about the care pathways of the general population of patients with chronic haematological malignancies. Secondary – to produce information resources suitable for testing in routine National Health Service practice. Design Population-based cohort of ≈ 8000 patients with chronic haematological malignancies, incorporating five nested work packages, each with its own individual design: (1) exploration of patient experiences: information and treatment decisions; (2) population-based analyses; (3) health economics; (4) development of information resources to support decision-making; and (5) patient well-being and decision-making survey. Setting This programme is predicated on the infrastructure of the United Kingdom’s Haematological Malignancy Research Network (www.hmrn.org); which provides ‘real-world’, robust, generalisable data to inform research and clinical practice, nationally and internationally. Set in Yorkshire and Humberside, the Haematological Malignancy Research Network’s catchment population of ≈ 4 million has a comparable sex, age, urban/rural, and area-based deprivation (Index of Multiple Deprivation, income domain) distribution to the United Kingdom as a whole; and in terms of ethnic diversity the region is centrally ranked, with around 80% of residents identifying as White British, 9% as Asian and 2% as black. Within the Haematological Malignancy Research Network, clinical practice adheres to national guidelines, and all patients with blood cancers are centrally diagnosed (≈ 2500 each year), tracked through their treatment pathways and linked to national databases (deaths, cancer registrations and Hospital Episode Statistics). Linked to the same national databases, the Haematological Malignancy Research Network also contains an age- and sex-matched general-population cohort. Participants Patients aged ≥ 18 years, resident in the study region, and diagnosed with chronic lymphocytic leukaemia, follicular lymphoma or myeloma. Methods Core Haematological Malignancy Research Network data were used to compare the hospital activity of patients with chronic lymphocytic leukaemia, follicular lymphoma and myeloma with that of the general population. Following additional linkages to genetic and clinical data, follicular lymphoma prognostic factors were examined. Two self-administered questionnaires addressing (1) quality of life and well-being and (2) decision-making were iteratively developed, piloted and deployed. Linkage to quality of life, clinical information and Hospital Episode Statistics enabled economic (myeloma) model development. In-depth interviews were conducted with 35 patients (10 alongside relatives). Results Trajectories of ≈ 8000 patients were mapped, and patient-pathway visualisations summarising individual and aggregate information were developed. As expected, patients with chronic blood cancers experienced higher levels of hospital activity than their general population counterparts, the largest effects being for myeloma. Following survey deployment, 3153 patients were recruited across 14 hospitals, 1282 with chronic lymphocytic leukaemia, follicular lymphoma or myeloma. Over half of the questionnaires were completed by patients on watch and wait; the remainder were completed during treatment or post-chemotherapy monitoring. Information gathered, coupled with in-depth interviews, demonstrated patients’ marked anxiety and fluctuating preferences for information sharing and decision-making, contingent on complex, inter-related factors. In turn, prognostic and microsimulation economic models were used to predict individual-level trajectories across multiple treatment lines, examining associated overall survival, costs and quality-adjusted life-years. Limitations Survey mapping to individual care pathways could not be completed because the COVID-19 pandemic delayed clinical data collection. Patients who attended clinics and participated in the survey were more likely than non-attenders to have had first-line chemotherapy, be slightly younger and live in more affluent areas. Conclusions This programme collated high-quality, population-based evidence. Previously lacking, this, coupled with new findings on preferences for information sharing and treatment decisions, provides the foundation for future research. Future work The translation of information accrued into resources suitable for testing in routine NHS practice is key. In this regard, COVID-19 has changed the communication landscape. The visualisations developed by this programme require further refinement/testing using participatory co-design with stakeholder groups. Underpinned by a suitable protocol applied within a single multidisciplinary team setting, prior to further evaluation within/outside the region, such outputs require testing in a cluster-randomised trial. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-0613-20002) and is published in full in Programme Grants for Applied Research ; Vol. 12, No. 5. See the NIHR Funding and Awards website for further award information.

Multiple myeloma is a bone marrow-based plasma cell tumour that develops from asymptomatic pre-cursor conditions smouldering myeloma and monoclonal gammopathy of uncertain significance and all are characterised by the presence of a monoclonal protein in the blood. Diagnosis and distinction between these conditions is based on blood tests, the bone marrow biopsy and cross sectional imaging. There are various risk stratification models that group patients with smouldering myeloma into risk groups based on risk of progression to symptomatic disease. Management is mainly observational for patients with smouldering myeloma although clinical trials for high-risk disease may be available. Restaging is required if evidence for progression.

This Good Practice Paper provides recommendations for the use of advanced imaging for earlier diagnosis and morbidity prevention in multiple myeloma. It describes how advanced imaging contributes to optimal healthcare resource utilisation by in newly diagnosed and relapsed myeloma, and provides a perspective on future directions of myeloma imaging, including machine learning assisted reporting.

Background The efficacy of consolidation and maintenance in the context of salvage autologous haematopoietic stem-cell transplantation (HSCT) for relapsed multiple myeloma remains unclear. We aimed to assess whether consolidation after salvage autologous HSCT, using ixazomib, thalidomide, and dexamethasone, followed by maintenance with single agent ixazomib is superior to observation. Methods This is an interim analysis of Myeloma XII (ACCorD; referred to as ACCorD hereafter), an open-label, randomised, controlled, phase 3 trial done at 79 hospitals in the UK. Eligible patients were aged 18 years or older, had relapsed multiple myeloma with measurable disease, an ECOG performance status of 2 or less with adequate renal, hepatobiliary, pulmonary, and cardiac function, and required treatment for first progressive disease occurring at least 12 months after first autologous HSCT. In a first randomisation, patients were assigned (1:1) to receive either conventional autologous HSCT with melphalan or augmented autologous HSCT with melphalan and ixazomib. In the second randomi sation, reported here, patients were assigned (1:1) to consolidation using ixazomib, thalidomide, and dexamethasone (oral ixazomib 4 mg per day on days 1, 8, and 15, oral thalidomide 100 mg per day on days 1-28, and oral dexamethasone 40 mg per day on days 1, 8, 15 and 22 of 28-day cycles), followed by maintenance with single agent ixazomib (oral ixazomib 4 mg per day on days 1, 8, and 15 of 28-day cycles until disease progression or intolerance), or observation. The primary endpoint was progression-free survival, analysed by intention-to-treat. Safety was analysed per-protocol. This study is registered with ISRCTN, ISRCTN10038996, and EudraCT, 2016-000905-35, and recruitment is complete. Findings Between Dec 12, 2017, and April 21, 2023, 206 patients entered the second randomisation (103 in the consolidation and maintenance group and 103 in the observation group). This prespecified interim analysis (data cutoff April 21, 2023), was done at a median follow-up of 27 months (IQR 13-38). Median progression-free survival was 20 months (95% CI 15-29) in the consolidation and maintenance group and 13 months (11-18) in the observation group (hazard ratio 0 center dot 55 [95% CI 0 center dot 39-0 center dot 78]; p=0 center dot 0006). Serious adverse events were reported in 29 (32%) of 92 patients in the consolidation and maintenance group compared with seven (7%) of 103 patients in the observation group. The most common serious adverse events were infections and infestations in both the consolidation and maintenance group and the observation group. The most common grade 3, 4, or 5 adverse events for patients in the consolidation and maintenance group were upper respiratory infection (seven [8%] of 92 patients). No deaths in the consolidation and maintenance group were deemed treatment related. Interpretation ACCorD provides evidence that an orally administered, deliverable, and tolerable post- salvage autologous HSCT treatment regimen can improve the durability of response for transplantation- eligible patients at first relapse. The findings are of relevance to patients who had durable disease control from autologous HSCT in the first line, representing a viable alternative to continuous parentally-administered relapse therapies. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Introduction: sASCT in multiple myeloma (MM) induces superior durability of response over non-transplant consolidation 1. Currently there is no prospective evidence for post-sASCT consolidation and maintenance. This is important given that most patients relapsing after first ASCT (ASCT1) are lenalidomide refractory (Len-Ref) following maintenance. The role of a proteasome inhibitor (PI) containing post-sASCT consolidation and maintenance strategy is explored in UK-MRA Myeloma XII (ACCoRD) trial using the second-generation oral PI, ixazomib. The results of a planned interim analysis (IA) of efficacy and safety are presented here.

The COVID-19 pandemic has had global healthcare impacts, including high mortality from SARS-CoV-2 infection in cancer patients; individuals with multiple myeloma (MM) are especially susceptible to poor outcomes. However, even for MM patients who avoided severe infection, the ramifications of the pandemic have been considerable. The consequences of necessary socio-geographical behavior adaptation, including prolonged shielding and interruptions in delivery of non-pandemic medical services are yet to be fully understood. Using a real-world dataset of 323 consecutive newly diagnosed MM patients in England, we investigated the impact of the COVID-19 pandemic on routes to myeloma diagnosis, disease stage at presentation and relevant clinical outcomes. We demonstrate increasing MM presentations via emergency services and increased rates of bony and extra-medullary disease. Differences were seen in choice of induction therapy and the proportion of eligible patients undertaking autologous stem cell transplantation. Whilst survival was statistically inferior for emergency presentations, significant survival differences have yet to be demonstrated for the entire cohort diagnosed during the pandemic, making extended follow-up critical in this group. This dataset highlights wide-ranging issues facing MM patients consequent of the COVID-19 pandemic, with full impacts for clinicians and policy-makers yet to be elucidated.

Daratumumab is a CD38-directed monoclonal antibody indicated to treat multiple myeloma (MM). Daratumumab was initially administered intravenously (IV), subsequently a subcutaneous (SC) formulation was developed to increase convenience of administration. The UK was an early adopter of SC daratumumab and, as such, this report provides consensus recommendations from a group of UK MM experts, with the aim of facilitating the transition from IV to SC daratumumab for other European healthcare providers. The switch from IV to SC daratumumab has been beneficial to patients and healthcare providers, as it simplifies treatment, reduces pressure on hospitals and can improve patients' quality of life.

The Myeloma X trial provided a platform to explore genetics in relation to systematic assessment of patient-reported outcomes at key points during salvage treatment in multiple myeloma (MM) patients. Blood DNA was obtained in 191 subjects for single nucleotide polymorphism (SNP) genotyping. By univariable analysis, the non-coding rs2562456 SNP, upstream of LINC00664, was associated with several relevant pain and health-related quality-of-life (HRQoL) scores at 100 days after allocation to consolidation with autologous stem cell transplantation or weekly cyclophosphamide. Presence of the minor (C) allele was associated with lower pain interference ( p = 0.014) and HRQoL pain ( p = 0.003), and higher HRQoL global health status ( p = 0.011) and physical functioning ( p = 0.007). These effects were not modified by treatment arm and were no longer significant at 6 months. Following induction therapy, the rs13361160 SNP near the CCT5 and FAM173B genes was associated with higher global health ( p = 0.027) and physical functioning ( p = 0.013). This exploratory study supports associations between subjective parameters in MM with SNPs previously identified in genome-wide association studies of pain. Conversely, SNPs in candidate genes involved in opioid and transporter pathways showed no effect. Further studies are warranted in well-defined cancer populations, and potentially assisted by whole genome sequencing with germline analysis in routine diagnostics in haematological cancers.

Abstract The COVID-19 pandemic has had global healthcare impacts, including high mortality from SARS-CoV-2 infection in cancer patients; individuals with multiple myeloma (MM) are es-pecially susceptible to poor outcomes. However, even for MM patients who avoided severe infection, the ramifications of the pandemic have been considerable. The consequences of necessary socio-geographical behavior adaptation, including prolonged shielding and inter-ruptions in delivery of non-pandemic medical services are yet to be fully understood. Using a real-world dataset of 323 consecutive newly diagnosed MM patients in England, we in-vestigated the impact of the COVID-19 pandemic on routes to myeloma diagnosis, disease stage at presentation and relevant clinical outcomes. We demonstrate increasing MM presentations via emergency services and increased rates of bony and extra-medullary dis-ease. Differences were seen in choice of induction therapy and the proportion of eligible patients undertaking autologous stem cell transplantation. Whilst survival was statistically inferior for emergency presentations, significant survival differences have yet to be demon-strated for the entire cohort diagnosed during the pandemic, making extended follow-up critical in this group. This dataset highlights wide-ranging issues facing MM patients conse-quent of the COVID-19 pandemic, with full impacts for clinicians and policy-makers yet to be elucidated.

SummaryPatients with haematological malignancies have a high risk of severe infection and death from SARS‐CoV‐2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS‐CoV‐2 infection and active haematological cancer. The primary end‐point was all‐cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1–2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96–1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09–5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08–2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti‐CD19/anti‐CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS‐CoV‐2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti‐CD19/anti‐CD20 treatments.

Chapter 2 in: E. Zamagni (ed.), Management of Bone Disease and Kidney Failure in Multiple Myeloma, https://doi.org/10.1007/978-3-030-63662-3_2

Infection with the novel coronavirus SARS-CoV-2, resulting in an acute respiratory disease (COVID-19), is the cause of the current pneumonia pandemic, with a rapid rise in cases being reported in the European Union and UK.1, 2 The UK index case was identified on January 31, 2020 and, given the rapid spread and high mortality rate of COVID-19, it is imperative to define the impact on patients with co-existing medical conditions.3 Multiple myeloma (MM), the second-most common haematological malignancy, is a cancer of the mature B-cell lineage, and is associated with both cellular and humoral immune dysfunction that renders patients susceptible to infections, especially of the respiratory tract.4-7 This, coupled with a median age at presentation of 70 years in a population with frequent co-existing medical conditions, means the outcomes of MM patients infected with COVID-19 warrants particular attention. We conducted a fully-anonymised prospective clinical audit where only MM patients with documented symptomatic COVID-19, whether managed in the inpatient or outpatient setting, were reported. All patients were tested within the secondary care setting and were receiving systemic anti-cancer therapy (SACT). At the time of analysis (May 18, 2020), 75 completed proformas from MM patients who tested swab-positive for COVID-19 had been received (Table I). The median age of COVID-19-positive MM patients was 73 years (range, 47–88), with 27·5% of patients >80 years of age. Where ethnicity details were available (n = 51), most (82%) were Caucasian, with 16% being Afro-Caribbean. 41% of patients were newly-diagnosed MM receiving frontline therapy (NDMM); 24% had relapsed from their frontline therapy and were now receiving second-line therapy (1st REL); and 35% had relapsed and/or refractory disease (RRMM). The median absolute lymphocyte count at presentation with COVID-19 symptoms was 600 cells/μl (range, 0–2500), with 90% of patients demonstrating hypo-gammaglobulinaemia affecting at least 1 sub-class (IgG> IgM>IgA). The male/female ratio was 1·5, but varied with age (<75 years ratio 2·33 vs. >75 years ratio 0·94) as a consequence of significant age difference between the groups (P = 0·049). The median time from the UK Index case to COVID-19 symptoms was 54 days (range, 23–88). 20·5% of patients did not have a temperature on presentation but did have a cough, and 16% reported GI symptoms, with 20·5% of patients acquiring COVID-19 whilst an inpatient for other reasons. 75% had evidence of pulmonary infiltrates primarily detected by chest radiograph. All but three patients were admitted for clinical care. Systemic anticancer therapy (SACT) was stopped a median of 0·5 days (range, 5–23) after the onset of COVID-19 symptoms. Only nine of 70 patients received critical care support, with five patients requiring non-invasive ventilation, two of whom escalated to invasive ventilation and four patients going straight to invasive ventilation, with all nine patients dying. Six patients had clinical/laboratory features of cytokine release syndrome.8, 9 One patient was treated with ruxolitinib, but did not survive; one patient received tocilizimab (recovered); and four patients received supportive care only, none of whom survived. Only one patient received treatment with hydroxychloroquine. Caution should be raised over the use of anecdotal experience to influence clinical practice, and even in these difficult times, we need to generate evidence from well-designed clinical trials. Currently, the UK mortality rate for COVID-19 is 14·5%, with an all-cancer mortality rate of 5·6% (https://coronavirus.data.gov.uk/). The impact of COVID-19 on specific cancers, especially blood cancers, is not known. In our cohort to date, 41 patients (54·6%) have died. The median time from symptom onset to death was 8·5 days (range, 0–23), and for those who have died, the median length of stay (LoS) was 7 days (range, 0–57), compared to those who survived COVID-19 infection who had a median time from symptom onset to discharge of 7 days (range 0–42) and a median LoS of 6·5 days (range, 0–21). The median age of patients who have died was significantly higher than those who survived [78 years (range, 51–88) compared to 66 (47–88); P = 0·017; Fig 1A]. 17 out of 24 (71%) patients >80 years died, compared to 24 out of 51 (47%) patients <80 years. This reflects the national mortality age impact. It is important to note a greater representation of females with MM who have died, which is at odds with the national picture. Co-existing medical conditions have been linked to outcomes from COVID-19.3 There was a median of 1 (range, 0–4) comorbidities in the group, and 0/1 comorbidities reported in 60% of the >80 year old cohort. Hypertension was the commonest comorbidity (41·3% of patients), and a greater level of comorbidity was seen in those who have succumbed to COVID-19 (Fig 1B). A disproportionate level of COVID-19-related mortality is noted in patients of Afro-Caribbean origin in our cohort (Fig 1C) compared to Caucasian patients, but extreme caution is advised in relation to over-interpreting this data, given the actual low numbers of patients of non-Caucasian origin (n = 10) reported in this audit despite the prevalence of MM.10 RRMM may be at greatest risk of an adverse outcome from COVID-19.11 The median time from diagnosis to COVID-19 infection was 28·3 months (range, 1–195), with no significant difference between those who survived and those who did not. However, 54·8% of symptomatic COVID-19 patients with NDMM did not survive, compared to 50% of RRMM. This may reflect a greater impact of tumour-induced immune suppression and infective risk associated with NDMM.12-14 This early review of emerging, real-world data highlights the impact of COVID-19 in patients with MM in the UK. There is a higher-than-expected mortality from concomitant viral infection, though this may represent the more vulnerable and symptomatic of MM patients presenting to secondary care and over-estimate the true mortality, given the absence of primary care data. There is currently insufficient data to extrapolate whether the type of SACT being received has any impact on the severity of infection, which may be important in determining longer-term management of MM patients during the COVID-19 pandemic.