The Tackling Early Morbidity and Mortality in Myeloma trial (TEAMM) trial recruited 977 newly diagnosed myeloma patients from 93 UK hospitals to assess the advantages and disadvantages of prophylactic antibiotics for the first 12 weeks. This paper analyses the 133 (14%) patients who had previously known precursor disease including monoclonal gammopathy of undetermined significance (MGUS) and smouldering myeloma (SMM), reporting the relative importance of blood-based biomarkers, imaging findings and symptoms in their management. Prior to progression with active myeloma, patients with precursor conditions had symptoms for five times longer than patients with no diagnosed precursor phase. Although only 29% of patients reported new myeloma-related symptoms developing after their first haematology appointment, 70% had a significant rise in paraprotein levels prior to progression. Likewise, risk scores for both MGUS and SMM increased prior to progression. Fractures occurred in 25% of patients despite being monitored for precursor disease. These fractures were difficult to predict as biomarkers lacked specificity and only 40% of patients reported back pain in combination with vertebral fractures. This study highlights the ongoing challenge of promptly recognising disease progression when using patient-reported symptoms and monoclonal immunoglobulin monitoring.

Introduction Frail myeloma (MM) patients remain at risk of greater toxicity and shorter survival outcomes. Approaches to improve this by therapy adaptation include delivering different therapeutic combinations or dose adjusting components of therapy. Understanding which of these approaches to adopt is timely as 4-drug combinations are now approved for transplant ineligible (TNE) patients but were only trialled in non-frail patients. Methods The UK-MRA, Myeloma XIV FiTNEss trial (NCT03720041) is a phase III, multi-centre, randomised controlled trial for newly diagnosed TNE MM patients. The primary objectives are to compare standard and frailty-score adapted (FA) induction therapy with an oral PI/IMiD combination (ixazomib, lenalidomide, dexamethasone, IRD) for 12 cycles and, after a second randomisation (R2), to compare maintenance R to IR. Frailty status was assessed using the full IMWG frailty score. The primary endpoint, early treatment cessation (ETC) in UNFIT/FRAIL patients within 60 days of R1, was reported at ASH 2024 with no significant difference, but there was significant heterogeneity in this outcome with UNFIT patients having a benefit from FA treatment (OR 0.34 [0.16,0.72])​ not seen in FRAIL patients (OR 1.33 [0.79,2.25]). With longer follow-up we now present data exploring the pathway and outcomes of UNFIT and FRAIL patients, including updated analysis of EFS, PFS and OS. Results The FiTNEss trial randomised 733 patients from 04/AUG/20 - 01/MAR/24 at 84 UK sites. 239 (32.6%) were UNFIT and 296 (40.4%) FRAIL. In the UNFIT group the median (IQR) age was 77 years (75-78), 56.9% were male, ISS was I in 25.9%, II 43.9% and III 30.1%, 13% had ECOG >=2. In the FRAIL group the median age was 81 years (78-84), 55.4% were male, ISS was I in 14.2%, II 48.6% and III 36.8%, 43.2% had ECOG >=2. Across the primary endpoint population (UNFIT/FRAIL combined) after median follow up of 26 (IQR 16,38) months (m) median EFS was not significantly different between FA and standard dosing (FA 2m [95% CI 1,3] vs standard 1m [1,2]). PFS and OS also appeared similar (median PFS: FA 23m [19,34] vs standard 27m [21,36] HR 1.12 [0.87,1.43], p=0.372; 3yr OS: FA 69.5% [61.9,75.9] vs standard 66.4% [59.2,72.7], HR 0.87 [0.63,1.20], p=0.399). Due to the heterogeneity in the ETC primary endpoint we performed subset analysis in UNFIT and FRAIL patients for EFS, PFS and OS. In UNFIT patients FA therapy was associated with improved EFS and OS (median EFS FA 5m [95% CI 3,9] vs standard 2m [1,4]; median PFS FA 34m [20,46] vs standard 37m [26,NR]; 3yr OS: FA 84.9% [75.4,91.0] vs standard 75.2% [65.1,82.7]). FRAIL patients had inferior outcomes across all endpoints compared to UNFIT patients and did not appear to gain any benefit from FA dosing (median EFS FA 1m [0,1] vs standard 1m [0,1]; median PFS FA 19m [14,26] vs standard 21m [16,33]; 3yr OS: FA 55.2% [43.6,65.3] vs standard 58.7% [48.1, 67.8]). Most EFS events were >=G3 non-haematological toxicities (most frequently infections and skin/subcutaneous disorders). These comprised a lower proportion of events in the FA group (UNFIT 70/104, 67.3%; FRAIL 92/138, 66.7%) compared to standard (UNFIT 78/104, 75.0%; FRAIL 105/140, 75.0%). FRAIL patients were more likely to have >=G4 haem toxicity, withdrawn or died as their EFS event, and these comprised a slightly higher proportion of events in the FA group, leading to the similar EFS in this group. FRAIL patients had a shorter median duration of induction therapy even with FA dosing (UNFIT: FA 12 cycles [95% CI NR] vs standard 12 [10,NR]; FRAIL: FA 7 [4,10] vs standard 9 [6,11]). FRAIL patients in both arms were much less likely to reach R2 (UNFIT: FA 55%, standard 46%; FRAIL: FA 29%, standard 30%). Unacceptable toxicity was the most reported reason for withdrawal from treatment. Conclusions Results from FiTNEss suggest that ETC, EFS and OS were improved by FA dosing in UNFIT but not FRAIL patients. In FRAIL patients, shorter durations of treatment and shorter EFS/PFS/OS persist with PI/IMiD combinations even with prospective treatment modifications. Data from other trials suggest anti-CD38/IMiD combinations may be better tolerated in FRAIL patients, with improved outcomes. Our data suggest the recently approved anti-CD38/IMiD/PI combinations should be used cautiously in FRAIL patients even with FA dosing strategies. Future studies should explore other approaches such as treatment switching for FRAIL patients with a suboptimal response.

Peripheral blood stem cell (PBSC) donation is the primary procedure used to collect haemopoietic stem and progenitor cells (HSPCs) for haemopoietic stem cell transplants (HSCT), however there is a clinical need to reduce collection times and achieve sufficient HSPC doses for successful engraftment. Short bouts of interval cycling transiently enrich peripheral blood with HSPCs and cytolytic natural killer (CD56dim NK) cells, which predict engraftment success and prevent post-transplant complications respectively. Despite this, feasible protocols for use during PBSC collections (≈ 3 h) have yet to be evaluated. In a randomised crossover design, 18 adults (9 young: 22.7 ± 3.2 years, 9 older: 65.2 ± 12.9 years) completed 3 × 3-h trials: high-intensity interval exercise (HIIE, 9 × 2-min cycling at 80–85

Peripheral blood stem cell (PBSC) donation is the primary procedure used to collect haemopoietic stem cells (HSCs) for transplantation in individuals with haematological malignancies. More than 90,000 HSC transplants take place globally each year, and there is an increasing need to guarantee HSC mobilisation, improve tolerability to apheresis, and optimise immune reconstitution. Currently, mobilisation of HSCs depends upon pharmacological agents, with donors inactive during their subsequent apheresis. A successful yield of HSCs is not always achieved, and greater efficiency of collection procedures would improve the donors’ safety and experience, along with the overall functioning of apheresis departments. The mobilisation of immune cells during bouts of exercise has been increasingly studied over the past 40 years. Exercise enriches peripheral blood with HSCs and immune cells such as cytolytic natural killer cells, and these may impact upon collection efficiency and patient outcomes following transplantation. Using exercise in conjunction with routine pharmaceutical agents may meet these needs. This article describes the impact of exercise on the quantity and engraftment potential of HSCs. Given that PBSC collections take on average 3–4 h per day per donor, and often consecutive days to complete, particular attention is paid to adopting interval exercise in this setting. Moreover, practical and safety considerations for allogeneic and autologous donors are discussed. ‘Intra-apheresis cycling’ is proposed as a feasible adjunctive strategy to evoke clinically significant improvements in the quality of the immune graft. Further research is needed to validate this concept in conjunction with routine mobilisation agents.

ABSTRACT:Functional high-risk (FHR) multiple myeloma (MM) is defined as an unexpected, early relapse (ER) of disease in the absence of baseline molecular or clinical risk factors (RF), making FHR MM inherently dependent on which RFs were assessed at diagnosis, and what treatment patients received. To establish the true incidence of FHR, we analyzed uniformly treated, transplant-eligible patients from the Myeloma-XI (MyXI) trial that had been profiled for the International Myeloma Society and Working Group (IMS/IMWG) defined high-risk cytogenetic aberrations (HRCA), and the SKY92 gene expression HR signature (GEP-HR). A total of 135 MyXI patients were studied, with a median follow-up of 88 months; 25 (18.5%) experienced ER, defined as relapse <18 months from maintenance randomization post-autologous stem-cell transplantation. Hereof, 15 (60%) were IMS/IMWG-HR at diagnosis, of whom 8 were also GEP-HR. Another 6 patients were GEP-HR only and would have been missed by IMS/IMWG-HR. Among 4 patients with IMS/IMWG- and GEP-standard risk, 2 had isolated HR markers at diagnosis, leaving only 2 patients (8% of ER; 1.5% of all) truly meeting all FHR-criteria. Combined IMS/IMWG-HR and GEP-HR profiling identified 84% of ER, and differentiated long-term outcome across all 135 patients: co-occurring IMS/IMWG and GEP-HR was associated with very short overall survival compared to the absence of both (HR = 13.1; 95% CI, 6.5-26.1, P < .0001), followed by GEP-HR only (HR = 5.1; 95% CI, 2.4-11.1, P < .0001) and IMS/IMWG-HR only (HR = 3.2; 95% CI, 1.6-6.2, P = .0007). Our results support more comprehensive baseline diagnostic profiling to identify those at risk of ER upfront. The trials were registered at the ISRCTN Registry as ISRCTN49407852 and at clinicaltrials.gov as #NCT01554852.

Chimeric antigen receptor (CAR) T cells represent a novel targeted approach to overcome deficits in the ability of the host immune system to detect and subsequently eradicate tumors. The identification of antigens expressed specifically on the surface of tumor cells is a critical first step for a targeted therapy that selectively targets cancer cells without affecting normal tissues. 5T4 is a tumor-associated antigen expressed on the cell surface of most solid tumors. However, very little is known about its expression in hematologic malignancies. In this study, we assess the expression of 5T4 in different types of leukemias, specifically acute myeloid leukemia (AML), and normal hematopoietic stem cells (HSC). We also provide an in vitro assessment of safety and efficacy of 5T4-targeting CAR T cells against HSCs and AML tumor cell lines. 5T4 expression was seen in about 50% of AML cases; AML with mutated nucleophosmin 1, AML-myelodysplasia-related, and AML not otherwise specified showed the highest percentage of 5T4+ cases. 5T4 CAR T cells efficiently and specifically killed AML tumor cell lines, including leukemic stem cells. Coculture of 5T4 CAR T cells with HSCs from healthy donors showed no impact on subsequent colony formation, thus confirming the safety profile of 5T4. A proof-of-concept study using a murine model for AML demonstrated that CAR T cells recognize 5T4 expressed on cells and can kill tumor cells both in vitro and in vivo. These results highlight 5T4 as a promising target for immune intervention in AML and that CAR T cells can be considered a powerful personalized therapeutic approach to treat AML.

Vaccines are less immunogenic in older adults, partly due to immunosenescence. Having previously shown that morning influenza vaccination may be more immunogenic in older adults (mean age 71), we assessed if this could be replicated in a younger cohort (mean age 57) and with a T-cell independent vaccine. This study examined whether diurnal timing of a single dose of Pneumovax (R) (PPV-23) and seasonal influenza vaccine influenced antibody responses in 140 healthy adults over the age of 50. Pneumococcal serotype-specific (PnPS) antibodies and Haemagglutination Inhibition Assays (HAI) were used to characterize antibody responses at Baseline, 1, 4, and 52 weeks post-vaccination. Protective thresholds were set at 0.35 mu g/mL for two-thirds of PnPS tested (WHO >= 8/12PnPS) and a titre of >= 40 HAI for H1N1, H3N2, and B/Victoria strains. Both AM and PM cohorts showed increased Pn-specific antibodies to one PPV-23 dose at weeks 1, 4, and 52; however, time of day did not significantly influence antibody responses. Baseline immunity for pneumococcus was high (57.1 % AM, 50.0 % PM had WHO >= 8/12PnPS), and immunity was maintained with at least 7/12 serotypes elevated at 52 weeks. Time of day did not alter short- or long-term influenza antibody responses. H1N1 had the highest baseline immunity (67.6 % AM, 48.6 % PM had >= 40 HAI) and the most increased responses at week 4 post-vaccination (92.8 % AM, 94.1 % PM) that were maintained at 52 weeks post-vaccination (91.7 % AM, 89.3 % PM). The poorest serotype immunity was for the B/Victoria strain at all time points. Although time of day did not influence vaccine immunogenicity in AM and PM cohorts, sustained cohort-wide antibody responses were demonstrated in an older population. Identifying 18 % of the total cohort exhibited suboptimal responses to pneumococcal or influenza vaccines underscores the imperative for enhancing vaccine efficacy within this age group to reduce morbidity and mortality.

Introduction: Multiple Myeloma (MM) is a heterogeneous disease making it difficult to accurately predict the disease course in individual patients. Staging systems in MM have evolved, firstly the International Staging System (ISS), then incorporation of genomic aberrations with revised-ISS. Recently, the IMWG agreed on consensus genomic staging of high-risk MM. However, no scoring system captures the nuances of the genetic landscape of each MM patient. In the era of genomic profiling, this information should be utilised to predict disease behaviour, which can be achieved through computational modelling. We recently developed and validated a model signalling network within B cells, which predicts pathway activation and protein abundance in B cells. We hypothesised that inclusion of genetic mutations from MM as parameter changes in this model could enable the creation of patient specific virtual cells that could improve disease stratification. Methods: Genetic data for 53 newly diagnosed MM patients, enrolled to the NCRI Myeloma XI was collected. The cohort were phenotypically high risk, relapsing within 30 months of maintenance randomisation. All patients achieved at least a partial response prior to relapse. Whole exome sequencing was conducted at presentation and relapse. All genetic mutations (SNPs, copy number variants, translocations) were verified for their oncogenic potential with OncoKB. Each mutation in each patient was mapped to a model parameter to create a set of 53 unique patient models in silico (e.g. gain of one copy of BCL2 increased the parameter representing BCL2 expression by 50%). To determine the apoptotic, and proliferative signalling state of the patient models 6-hour simulation was performed and the predicted abundance of cytoplasmic Smac, cytochrome C and cadherin-1 was stored. Patients were grouped according to their predicted signalling state, namely anti-apoptotic (AA, n=16), pro-proliferative (PP, n=11), anti-apoptotic and pro-proliferative (AAPP, n=15) and non-proliferative or apoptotic (NAP, n=11). We compared progression-free survival (PFS) in days between different groups using Cox regression for Hazard ratios (HR) and Log-Rank test for p-values. Results: As a benchmark we first evaluated the ISS in our cohort. ISS II versus ISS I was associated with a significantly worse PFS (HR 2.27 95% CI 1.07-4.8, p=0.032) as well as ISS III (HR 2.45 CI 1.13-5.31 p=0.024). However, ISS II was not significantly different from ISS III, likely due to the phenotypic high-risk cohort assessed. High-risk lesions del(17p), gain(1q), del(1p), (t(4;14), t(14;16), t(14;20) and neutral lesions, del(13q), HRD, t(6;14), t(11;14) and t(MYC), were all non-significant predictors of progression (p>0.05). Maintenance strategy (lenalidomide vs observation) was also not a significant predictor of outcome, consistent with the phenotypic behaviour. We then applied the model-driven signalling state stratification (AA, PP, AAPP, NAP) and found model stratification alone significantly predicted PFS (p=0.047). The PP group was associated with the longest PFS and the NAP group had the shortest (HR 3.33 CI 1.37-8.11, p=0.008). No HR genetic lesions were noted in the PP group, compared to 2/11 (18%), 4/16 (25%) and 7/15 (47%) for the NAP, AA and AAPP groups respectively. To incorporate modelling with existing prognostic tools we combined all good prognosis patient groups (ISS I [n=13], and PP patients [n=11]) into one group and compared it to the rest. This stratification method identified 9/53 (17%) patients with high ISS (II/III), but good prognosis predicted through modelling, and assigned them to the low-risk group. The remaining high risk patients (n=29) had a significantly higher HR of 2.21 for shorter PFS (CI 1.24-3.94, p=0.007). Conclusion:We show that computational modelling can be utilised to stratify MM patients into both good and poor prognostic groups in ways that improve on previous staging systems. Furthermore, this has been illustrated within a phenotypical high-risk cohort, emphasising its ability to uncover distinct subgroups in previously hard to classify patients. This approach provides the foundation for a novel approach to improving treatment decisions, developing personalised approaches such as treatment intensification based on the full genetic profile of an individual patient. Characterising the signalling state in a larger cohort and predicting response to treatment is underway.

Introduction: Older and frailer patients with multiple myeloma (MM) are less able to tolerate some therapies which may explain the inferior health outcomes they experience. The UK Myeloma Research Alliance Myeloma XIV FiTNEss trial (NCT0372004) is a phase III, multi-centre, randomised controlled trial for newly diagnosed MM patients not eligible for stem cell transplant that compares a standard (reactive) therapeutic dosing strategy (RT) to a pre-emptive frailty-adjusted dosing strategy (FA). FA uses IMWG-based scores to determine patients' level of frailty and adapts the dosing strategy accordingly in an effort to reduce toxicity and early treatment cessation. We conducted an economic evaluation alongside the FiTNEss clinical trial to determine the value of FA vs RT in Unfit/Frail patients over 12 months. Methods: The FiTNEss trial randomised newly diagnosed MM patients to either standard reactive dose modification in light of toxicity (RT) vs upfront pre-emptive dose-modification according to IMWG FS (FA), of induction therapy comprising the oral triplet ixazomib, lenalidomide and dexamethasone (IRd). The primary end point of the first randomisation was to compare early treatment cessation of induction therapy delivery with the triplet IRd between patient cohorts. The primary endpoint of the second randomisation was to compare progression free survival for maintenance lenalidomide (R) plus placebo and lenalidomide plus ixazomib (IR). The economic evaluation adopted the cost-utility framework and presents cost per quality-adjusted life year (QALY). Health-related quality of life (HRQoL) was captured on the EQ-5D-3L measure at baseline, 2, 6 and 12 months. Health care resource use was captured using patient reported forms at the same time points, supplemented by hospital incident forms. Costs included resources required for the frailty assessment, medication costs (including second line therapies for those progressing or stopping first line therapy), primary care costs (e.g. GP visits) and secondary care costs (e.g. hospital visits and stays). We conducted a complete case (CC) analysis, using cases who had provided full cost and HRQoL follow-up data, and an intention-to-treat (ITT) analysis using multiple imputation to deal with missing data. Estimates were adjusted for trial minimisation factors. We present cost and QALYs per trial arm and incremental cost-effectiveness ratios (ICERs). Sampling uncertainty is characterised in the probability of cost-effectiveness given the UK willingness to pay for QALY gains (£20,000-£30,000). Results: The FiTNEss trial recruited 733 patients from 04/08/2020 until 01/03/2024 from 84 sites in the UK; 535 patients were Unfit/Frail. The cost of the frailty assessment was modest (£28.50 based on an assumed 30 minutes of research nurse time). A total of 163 patients were included in the CC sample. The number of treatment cycles completed was slightly higher among Unfit/Frail in the FA arm (7.84 [95%CI 7.3:8.39] vs 7.73 [95%CI 7.19:8.27], p=0.78). Mean per patient primary care costs were lower in the FA arm (£107 [95%CI £75:£138] vs £194 [95%CI £112:£276], p=0.05); but mean secondary care costs were higher in the FA arm (£3,582 [95%CI £2324:£4841] vs £2,036 [95%CI £1295:£2777], p=0.04), driven by higher unplanned hospital admitted days. The adjusted differences in costs and QALYs between trial arms for the CC analysis were £7,431 [95%CI £-3532:£18394, p=0.14] and 0.072 ([95%CI 0.022:0.141], p=0.07) (ICER = £103,208), respectively; and for the ITT analysis were £250 [95%CI £-6841:£7340, p=0.95] and 0.02 ([95%CI -0.021:0.06], p=0.35) (ICER = £12,943), respectively. Thus, FA was more costly on average when considering medication and health care use costs but offered QALY gains over RT. At the UK cost-effectiveness threshold of £20,000-30,000 FA has a 52-54% probability of cost-effectiveness. Conclusions: This preliminary analysis suggests that frailty-adjustment of induction therapy in newly diagnosed TNE MM is likely to lead to non-trivial benefits in QALYs over 12 months, but higher levels of secondary care use and medication costs compared to standard dosing. Based on the ITT analysis, the FA strategy is likely to be considered cost-effective in Unfit/Frail patients. Future planned research extrapolating HRQoL benefits over a longer time horizon, where cheaper maintenance therapies are used, may give a more accurate estimate of the value of FA.

Introduction The UKMRA/NCRI Myeloma XI+ phase III randomized trial for NDMM patients compared intensified induction with a carfilzomib containing quadruplet (KRdc) vs a response-adapted approach of sequential triplet therapies. An interim analysis at a median of 35 months follow-up demonstrated a significant improvement in progression-free survival in the KRdc group (HR 0.63, 95% CI 0.51, 0.76, p <0.001). Here we present updated analysis after a median 102 months of follow up, including analysis of the co-primary endpoint overall survival. Methods Using an adaptive trial design the Myeloma XI trial, which initially randomized patients between CRd and CTd, was amended to randomly assign patients 2:1:1 between KRdc, CRd and CTd (Myeloma XI+). KRdc was given in 28 day cycles (carfilzomib (K) 36mg/m2 IV d1-2, 8-9,15-16 (20mg/m2 #1d1-2), lenalidomide (R) 25mg PO d1-21, dexamethasone (d) 40mg PO d1-4,8-9,15-16, cyclophosphamide (C) 500mg PO d1,8), CRd (28d, C 500mg PO d1,8, R 25mg PO d1-21, D 40mg PO d1-4, 12-15) and CTd (21d, C 500mg PO d1,8,15 thalidomide 100-200mg PO daily, D 40mg PO d1-4,12-15). Induction regimens were continued for a minimum of 4 cycles and to maximum response. Suboptimal responders (MR/PR) to CTd/CRd were randomized between pre-transplant intensification with a proteasome inhibitor (bortezomib, CVD) containing triplet or no further therapy prior to ASCT, patients with refractory disease (SD/PD) all received CVD. For all patients a maintenance randomization post ASCT compared lenalidomide to observation. Centrally analysed cytogenetic data was available for a representative subset of patients. High-risk (HiR) was defined as presence of t(4;14), t(14;16), t(14;20), del(17p) or gain(1q) and ultra-high risk (UHiR) the presence of more than one lesion. MRD assessment was performed using next generation flow with a median sensitivity of 2x10-5. Results 1056 patients underwent induction randomization, allocated to KRdc n=526, CTd n=265 and CRd n=265. The groups were well matched for baseline variables with median age 61 (range 33-75). No change in the toxicity profile emerged with long-term follow up. KRdc was associated with a significantly longer median PFS than triplet therapy, KRdc 56 vs CTd/CRd 37 months (HR 0.69, 95%CI 0.60, 0.80, p<0.001). Improved PFS was seen in all cytogenetic risk groups: SR median KRdc 64 vs CTd/CRd 42m (HR 0.71, 95%CI 0.51, 1.00), HiR 45 vs 36m (HR 0.70, 95%CI 0.47, 1.03), UHiR 34 vs 20m (HR 0.49, 95%CI 0.21, 1.12). MRD negativity was achieved in 26.9% of those tested at the end of induction (KRdc 38.5% vs CRd 16.3% vs CTd 10.8%) and in 47.7% after ASCT (KRdc 57.0%, CRd 36.7%, CTd 37.7%). MRD negative status was associated with improved PFS with all regimens and KRdc was associated with improved outcomes compared to CRd/CTd even in those achieving MRD negativity. Early achievement of MRD negativity with KRdc (after induction) was associated with improved PFS compared to those who achieved MRD- after ASCT. Analysis of OS for contemporaneously randomised patients was numerically longer with KRdc vs CTd/CRd (OS at 60 months 76% vs 71%, HR 0.87, 95%CI 0.72, 1.06, p=0.168). As the trial closed prior to the planned event-driven analysis (419/466 of required contemporary deaths) due to funding constraints, resulting in some loss of power for the OS analysis, an additional OS analysis was performed incorporating all patients randomised across the study (KRdc n=526, CTd n=1021, CRd n=1021) with appropriate adjustment for temporal changes in the control group. These data suggested KRdc significantly prolonged OS compared to CTd/CRd (OS at 60 months 76% vs 68%; HR 0.80, 95%CI 0.67, 0.95, p=0.011). The greatest OS benefit was seen in patient with ISS stage 3 and HiR/UHiR disease. PFS and OS results were consistent when an optimal control group (i.e. excluding those randomised to no CVD if PR/MR) was used. Conclusions The addition of carfilzomib to an immunomodulatory agent, dexamethasone and cyclophosphamide triplet was associated with deeper responses and a significantly longer PFS. OS was significantly improved when including non-contemporaneous controls, adjusted for temporal trends. This suggests a clinically significant improvement in overall survival and emphasises the importance of early combination of PI and IMID therapy rather than a response adapted approach, with particular benefit in patients with aggressive disease defined as HiR or UHiR.

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 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.

Introduction In the phase III UKMRA/NCRI Myeloma XI trial 1248 patients were randomised between lenalidomide maintenance and observation after induction therapy and ASCT. At a median of 31 months (m) follow-up there was a significant improvement in progression free survival (PFS) and overall survival (OS). Median PFS was 57m (95%CI 50-not reached) in the lenalidomide group and 30m (25-32) in the observation group (HR 0·48 [95%CI 0·40, 0·58]; p<0·0001 and 3-year OS was 87·5% [95%Cl 84·3-90·7] with lenalidomide and 80·2% [95%CI 76·0, 84·4] with observation; HR 0·69 [95% CI 0·52-0·93]; p=0·014. Here we present updated analysis after a median of 101 months follow up and explore outcomes by subgroups including transplant eligibility, MRD status, cytogenetic risk and duration of therapy. Methods Myeloma XI was a phase III trial with a pathway for transplant eligible (TE) newly diagnosed myeloma patients who, after immunomodulatory agent-based induction therapy and autologous stem cell transplant, were randomised between lenalidomide maintenance (Len, 10mg 21/28 days planned to continue till disease progression) or observation (Obs). Centrally analysed cytogenetic data was available for a representative subset of patients. High-risk was defined as presence of t(4;14), t(14;16), t(14;20), del(17p) or gain(1q) and ultra-high risk the presence of more than one lesion. MRD assessment was performed using next generation flow cytometry with a median sensitivity of 2x10-5. Results After a median of 101m of follow up lenalidomide maintenance was associated with a significantly prolonged median PFS 33 vs 66m, HR 0.57 [95% CI 0.50, 0.65], p<0.001. This improvement in PFS was consistent across cytogenetic risk groups (SR median PFS 37 vs 83m, HR 0.49 [95%CI 0.37, 0.66], p<0.001, HiR 29 vs 59m, HR 0.45 [95%CI 0.31, 0.66], p<0.001, UHiR 11 vs 23m, HR 0.50 [95%CI 0.28, 0.88]), p=0.017. Median overall survival was not significantly different in the overall population (116 vs 130m, HR 0.91 [95%CI 0.77, 1.09], p=0.316) but there was evidence of heterogeneity by genetic risk status with those patients having only one cytogenetic lesion having a significant OS benefit (SR OS at 7 years 67% vs 72%, HR 0.90 [95% CI 0.61, 1.34], HiR 42 vs 64%, HR 0.58 [95% CI 0.37, 0.90], UHiR 25 vs 25%, HR 0.91 [95% CI 0.46, 1.79]). MRD negative status at both ASCT+3m and ASCT+9m timepoints was strongly associated with improved PFS (ASCT+3m HR 0.55 [95%CI 0.46, 0.65], ASCT+9m HR 0.41 [95%CI 0.31, 0.54]) and OS (ASCT+3m HR 0.72 [95%CI 0.58, 0.89], ASCT+9m HR 0.52 [0.36, 0.75]). There was evidence of benefit of lenalidomide maintenance over observation in the MRD positive group for both PFS and OS and in the MRD negative group for PFS but not OS. Patients converting to MRD negativity by 9m appeared to have similar long outcomes to those achieving MRD negativity at the earlier time point. Multiple cut-point analysis confirmed previous findings suggesting a benefit for lenalidomide maintenance beyond 4-5 years in the overall population. There was no evidence of an adverse impact on overall survival with longer duration therapy. For patients MRD negative at the start of maintenance the benefit of ongoing maintenance appeared to lose significance earlier, after 3 years. With extended follow-up the median duration of maintenance is 36 cycles [range 1-146]. Around half of patients stopping maintenance did so due to disease progression (51.5%). In the remainder, the most common reason cited was toxicity (19.6%). 79% of patients required a lenalidomide dose modification during their maintenance course. No new specific toxicity signals were identified with longer-term follow up. Cumulative incidence of second primary malignancies at 8 years was 7.0% (95%CI 4.79%, 9.12%) in the observation arm and 12.4% (95%CI 10.13%, 14.71%) in the lenalidomide arm. Conclusions Taken together these data can help define the optimal maintenance strategy for different patient groups. For patients with standard risk disease who become MRD negative after ASCT, limited duration maintenance approaches could be considered and should be evaluated in randomised studies. Patients with single high-risk lesions appear to have the greatest benefit, with an overall survival benefit from maintenance continued to progression. Patients with UHiR disease and those MRD positive at 9 months after ASCT have poor long-term outcomes and should be considered for combination maintenance approaches.

Treatment advances have greatly improved survival, but myeloma is among the worst of all cancers for delayed diagnosis, causing serious morbidities and early deaths. This delay is largely because the symptom profile of myeloma has very low specificity, and in primary care, myeloma is rare. However, initiating the journey to diagnosis simply requires considering myeloma and sending blood to test for monoclonal immunoglobulin. Laboratory tests reliably detect monoclonal immunoglobulin, which is present in 99% of myeloma cases, so why do health care systems have such a problem with delayed diagnosis? The Myeloma UK early diagnosis programme has brought together diverse expertise to investigate this problem, and this article was prepared by the programme's working group for laboratory best practice. It reviews evidence for test requesting, analysis and reporting, for which there is large variation in practice across the United Kingdom. It presents a 'GP Myeloma diagnostic tool' and how it can be integrated into laboratory practice alongside a laboratory best practice tool. It proposes improved requesting and integration with haematology services for reporting and interpretation. Here the laboratory has a central role in creating efficient and cost-effective pathways for appropriate and timely bone marrow examination for myeloma diagnosis.

Neutrophils, pivotal cells of innate and adaptive immune responses, employ reactive oxygen species (ROS) to combat pathogens and control gene expression. Paracetamol (acetaminophen) is widely used as an analgesic and antipyretic medication, yet its precise mechanisms of action are not yet fully understood. Here, we investigate the impact of both ingested and in-vitro paracetamol on neutrophil ROS activity, using flow cytometry and antioxidant assays. Our studies reveal that paracetamol significantly suppresses ROS activity ex-vivo in the short term. Additionally, both paracetamol and its metabolite N-acetyl-p-benzoquinone imine exhibited direct in vitro antioxidant effects, and paracetamol suppressed neutrophil extracellular trap formation ex vivo. These findings suggest a connection between paracetamol use and altered neutrophil responses, with potential implications for use in some patient groups, such as immunocompromised individuals. Further investigation into paracetamol's effects on neutrophil antimicrobial functions is warranted to elucidate possible risks, particularly when taken frequently or in conjunction with other treatments such as vaccinations.

Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day + 100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.