Abstract Patients with multiple myeloma are frequently exposed to prolonged, multiline and multidrug treatments, factors that may substantially influence overall health, physical reserve, and physiological resilience. Imaging of organs that are captured by whole-body scans can be opportunistically interrogated to derive direct, quantitative measures of body composition. Advances and standardization of whole-body magnetic resonance imaging (WBMRI) together with recent improvements in artificial intelligence (AI) methodologies for automated organ and tissue segmentation presents an opportunity to complement accurate disease assessments with body composition metrics. We report, to our knowledge, for the first time, development of an AI-based pipeline to enable automated quantitative image-derived phenotypes in nondiseased tissue from WBMRI in patients with multiple myeloma. We have demonstrated that a deep-learning pipeline can derive body composition metrics from routinely acquired clinical WBMRI. Throughout treatment, significant longitudinal changes were observed (P< .001), characterized by a decrease in abdominal skeletal muscle (ASM) alongside transient increases in abdominal subcutaneous and visceral adipose tissue. We have also shown that greater reserves of ASM (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.40-0.89) and abdominal subcutaneous adipose tissue (HR, 0.67; 95% CI, 0.46-0.98) at baseline are associated with better progression-free survival. Conversely increases in visceral adipose tissue over time was associated with inferior progression-free survival (HR, 2.89; 95% CI, 1.65-5.09). These findings support opportunistic body composition phenotyping from diagnostic WBMRI as a scalable biomarker for risk stratification (concordance index, 0.725) and mechanistic study. This trial was registered at www.clinicaltrials.gov as NCT02403102.

There is an ongoing need for accessible combination therapies for patients with relapsed-refractory multiple myeloma (RRMM), alongside a growing interest in understanding their immunological effects, particularly on T-cell populations. Myeloma UK (MUK) MUKseven (NCT02406222) was an academic, UK multicentre randomized controlled, open-label phase 2 trial. The planned sample size was 250 patients but recruitment was stopped early due to changes in standard of care. Between 2016 and 2018, 104 RRMM patients from 26 UK hospitals were recruited and randomized to receive cyclophosphamide, pomalidomide, and dexamethasone (CPd) or pomalidomide and dexamethasone (Pd) using minimization. Fifty-four participants in each arm were analysed. The primary end-point, progression-free survival (PFS) was not met with median 6.9 months (95% Confidence Interval (CI): 5.7-10.4) for CPd versus 4.6 months for Pd (95% CI: 3.5-7.4), although not significant; reflecting underpowering from early closure. CPd showed a higher overall response rate, and toxicity was comparable to previously reported Pd regimens. Peripheral blood T-cell analysis revealed stronger and more sustained enrichment of CD3+ T cells, HLA-DR-positive CD8+ and CD8+ effector memory cells in the CPd arm. Pretreatment CD4+ T-cell levels were identified as a prognostic PFS marker. In summary, our results demonstrate significant effects of cycloaddition to Pd on response and T-cell composition.

Therapies for multiple myeloma (MM) have advanced; however, disparity in healthcare outcomes remains. Barriers to clinical trial enrollment contribute to this disparity and result in recruiting unrepresentative groups of patients, depriving patients of opportunities to benefit from experimental treatments, and causing incompletion of some trials due to insufficient accrual rates. This study aimed to identify geographic inequalities in clinical trial participation and develop a comprehensive list of barriers (factors preventing participation) to and facilitators (factors enabling improvements) of patient enrollment in MM clinical trials. Geographic data were collected for MM trials registered between 2011 and 2021 to determine the number of trials and recruitment rates in different regions. Of the trials identified, 61% recruited patients from the US; 24%, 14%, and 13% recruited patients from Western Europe, Southern Europe, and Eastern Asia, respectively. Other geographic regions were less involved in MM clinical trials, highlighting global inequality in MM clinical research. Barriers to and facilitators of patient enrollment in MM trials were identified through a systematic literature review and broadly categorized into 4 domains: clinical (eg, eligibility criteria), patient specific (eg, socioeconomics), physician specific (eg, awareness of trials), and structural (eg, regulatory environment). These domains were presented to stakeholders, who were from various backgrounds and geographic regions, to ascertain which were most relevant to patients with MM globally. Recommendations were identified, with unanimous support from interviewees, and have the most potential for global application. The application of these findings will help overcome the many barriers to enrollment in MM clinical trials.

Immunomodulatory drugs (IMiDs) are a cornerstone of multiple myeloma treatment and newer cereblon E3 ligase modulating drugs (CELMoDs) are in clinical trials. However, a major barrier to improving patient outcomes is the inevitable development of resistance to these agents. To explore the mechanisms underlying IMiD/CELMoD resistance, and identify novel targets for treatment, human cell line models of acquired IMiD/CELMoD resistance were generated. Quantitative proteome analysis of these models identified common changes in lipid synthesis proteins and glucose labelling experiments confirmed altered lipid flux. Proteomic analysis of paired patient samples, from diagnosis and relapse on IMiD, suggested similar changes in lipid pathways. A genome wide CRISPR screen performed in a human multiple myeloma cell line with acquired CELMoD resistance identified dependencies in the lipid pathway genes Stearoyl-CoA Desaturase (SCD) and Membrane Bound Transcription Factor Peptidase Site 1 (MBTPS1). This work has led to novel insights into lipid pathway changes in the IMiD/CELMoD-resistant state which may represent targetable cancer cell vulnerabilities.

Objective New bone pain raising concern for progressive disease in patients with multiple myeloma (MM), even when biochemical parameters are stable, can trigger requests for whole body imaging as disease can become non secretory at relapse. Our study aims to investigate whether targeted magnetic resonance imaging (MRI) can safely inform patient management in this setting. Methods We conducted a retrospective, single centre analysis of targeted MRI scans performed to investigate pain in biochemically stable MM patients, over 2 years. Patients with known non/oligosecretory disease or second cancers were excluded. Results 134 scans were included, from 111 patients. 112(84%) scans covered one body area, while 22(16%) covered 2 areas. The most common finding was degenerative change on 57(43%) scans, followed by fractures on 52(39%) scans. Only one fracture related to progressing disease. 97(72%) scans showed no active disease. Of the 37(28%) scans showing active disease, 21(16%) demonstrated new/increasing lesions. Whole-body imaging was subsequently requested in 12 cases (9%). Targeted scans triggered active intervention in a total of 28 patients. 50 patients (having 57 scans) had no recurrence on follow-up (median 26, range 2–40 months). Targeted MRI had a sensitivity of 96% and specificity of 90%. Conclusion In MM patients presenting with new pain in the absence of biochemical progression, targeted MRI scans safely inform clinical decision making, reducing the need for whole-body MRI and reducing scan duration for patients in pain.

External comparator cohort (ECC) studies with real-world data (RWD) may provide more reliable estimates of treatment differences compared to single-arm trials (SAT), yet they face limitations such as selection bias and data heterogeneity. This study assessed the perceived strength of evidence of ECC studies compared to SAT and randomized controlled studies (RCT). The study included healthcare professionals (HCP) from the European Hematology Association (EHA), the European Society for Medical Oncology (ESMO), and assessors from international regulatory agencies (RA). A conjoint analysis evaluated strength of evidence ratings for establishing an effect on OS for different hypothetical scenarios, based on different designs, RWD quality, and observed OS improvement, for a new cancer treatment for advanced disease and no effective treatments. Participants from HCP organizations rated RWD studies favorably (advantages outweigh disadvantages) more frequently (47.6%; n = 103) compared to RA participants (12.9%; n = 116). Compared to a SAT, a high-quality RWD ECC study showing a 1.5-month and 3-month OS improvement had 2.7 (95% CI: 1.9-3.8) and 14.7 (95% CI: 10.0-21.5) times higher odds of receiving a higher strength of evidence rating, respectively. The OR for RCT v. SAT was 36.4 (95% CI: 24.0-55.2) and 358.4 (95% CI: 217.3-591.3), respectively. Strength of evidence ratings were associated with maximum acceptable risk of severe or symptomatic toxicity. In conclusion, when evaluating the OS of new therapies, ECC studies with RWD, especially when based on high-quality RWD or demonstrating a larger OS benefit, were rated as more convincing than SAT without a formal control.

Despite therapeutic advances in B-cell malignancies, many patients continue to experience relapse or refractory disease, highlighting an unmet need for novel drug targets. The high attrition rate of drug development programs, however, represents a productivity-limiting step. To prioritize candidate drug targets, we used Mendelian randomization to evaluate causal associations between 2923 circulating proteins and 6 B-cell malignancies (22 922 cases and 388 978 controls). We identified 27 protein-disease associations, including TNFSF13 (APRIL) and TNFRS13B (TACI) in multiple myeloma, CD40 in Hodgkin lymphoma, and FAS in chronic lymphocytic leukemia. All results are interactively accessible via our R/Shiny application (https://software.icr.ac.uk/app/mrcan). Integrating single-cell RNA sequencing from 183 355 hematolymphoid cells, Bayesian colocalization, and clinical trial evidence, we prioritized 23 proteins as candidate drug targets. This study demonstrates the potential of human genetics to guide therapeutic discovery for B-cell neoplasia.

Outcomes for patients with multiple myeloma have improved substantially over the past two decades, with median overall survival more than doubling in many cohorts. Management of smouldering myeloma has also shifted, with randomised trials demonstrating that early intervention in high-risk disease delays progression and improves survival compared with observation alone. Imaging diagnostics must therefore evolve in parallel to provide minimally invasive, sensitive and quantitative insights into disease for patients who will live with myeloma for many years. Here we review the latest evidence for WB-MRI in myeloma, outline current guideline recommendations, and consider future directions.

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.

PURPOSE Survival for patients with multiple myeloma (MM) has improved but outcomes remain heterogeneous. Consistent diagnostic identification of high-risk disease is desirable to address unmet patient need. The aim was to investigate the consistency of association of co-occurrence of high-risk cytogenetic abnormalities (HRCAs) with prognosis in patients with newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM), and across a range of treatment modalities. METHODS A systematic review of randomized controlled trials of MM that reported testing for HRCA between January 1, 2000, and December 9, 2021, was performed. Groups were contacted and asked to locally perform a novel, federated analysis of their data for single hit (one HRCA) and double hit (≥two HRCAs), using a centrally provided algorithm. Analysis results were centrally collated and meta-analyzed to assess the hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) for one/≥two HRCAs across patient subgroups using random-effects models. RESULTS Twenty-four trials including 13,926 patients were included. The median age of participants was 66.5 years (IQR, 59-72) and 56.5% were male (IQR, 52-60). The HR for PFS was 2.28 (95% CI, 2.05 to 2.54) for patients with ≥two HRCAs and 1.51 (95% CI, 1.38 to 1.65) for patients with one HRCA. The HR for OS was 2.94 (95% CI, 2.49 to 3.47) and 1.69 (95% CI, 1.52 to 1.88) for the two subgroups, respectively. In studies initiated since 2015, the effect abides (≥two HRCA PFS, HR, 2.39 [95% CI, 1.96 to 2.91]; OS, 3.10 [95% CI, 2.10 to 4.60]) both for NDMM and RRMM. Heterogeneity related to transplant eligibility and relapsed/refractory status was as expected. CONCLUSION The association of ≥two HRCAs with the poorest outcome in NDMM and RRMM, and across treatment modalities, as demonstrated here for the first time to our knowledge, allows for more focused development of novel approaches to these patients with high unmet need.

OBJECTIVES:Clinical translation of advanced MRI techniques can be hindered by the challenges of performing standardized multicentre imaging trials. This work aims to develop and demonstrate an automated tool for monitoring imaging protocol deviations, enabling corrective action to be taken. METHODS:A Python-based tool, integrated into the imaging repository XNAT, was developed to compare DICOM series with an agreed imaging protocol, highlighting missing series and parameter deviations. This was demonstrated through retrospective analysis of a prospectively acquired dataset from a ten-site whole-body (WB) MRI study of patients with multiple myeloma. The acquired data were compared to the relevant radiological guidelines and to the site-specific imaging protocols agreed for the study. RESULTS:The rate of technical software failure was 0% across 174 examinations from 10 sites. The clinical guidelines were followed in 87.9% of examinations and compliance with the site-specific imaging protocol was greater than 75.0% for all parameters. Common deviations included number of averages for diffusion-weighted imaging (DWI) and repetition time for DWI and Dixon: 85.2%, 81.7%, and 75.1%, respectively. There was a statistically significant correlation between protocol compliance and overall exam radiological image quality. CONCLUSIONS:Repository-integrated software is presented for automated monitoring of imaging protocol compliance to support standardization in multicentre studies and clinical translation. ADVANCES IN KNOWLEDGE:This study presents a novel open-source repository-integrated software tool for automatically monitoring compliance with the expected imaging protocol. Standardized acquisition protocols are crucial in multicentre imaging studies and this tool has the potential to enhance research outcomes and support clinical translation.

JNJ-5322 is a novel, next-generation trispecific antibody with capabilities to target dual myeloma antigens with a single molecule, and contains novel B-cell maturation antigen (BCMA), G protein–coupled receptor class C group 5 member D (GPRC5D), and CD3 binding domains. JNJ-5322's binding to both BCMA and GPRC5D results in improved binding avidity that may enhance efficacy by overcoming clonal heterogeneity and preventing antigen escape. The first-in-human study (NCT05652335) in patients with relapsed/refractory multiple myeloma (RRMM) showed an improved or similar safety profile of JNJ-5322 compared with BCMA/GPRC5D bispecific antibodies (BsAbs) as monotherapy or in combination, and an overall response rate (ORR) of 100.0% at the recommended phase 2 dose (RP2D) in BCMA/GPRC5D naive patients. These data were supported by pharmacokinetic and exposure–response analyses that led to selection and dose optimization of the RP2D (100 mg every 4 weeks [Q4W]) and step-up dose (SUD; 5 mg). Here, we present updated safety and efficacy results of JNJ-5322 at the RP2D from part 1 of the ongoing phase 1 study. Dose escalation/expansion cohorts enrolled patients with RRMM who were triple-class exposed to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. The primary objectives were to identify the RP2D and to assess safety at the RP2D. Treatment-emergent adverse events (TEAEs) were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. ORR was assessed by IMWG criteria. Minimal residual disease (MRD) negativity was assessed at a threshold of 10–5 using next-generation sequencing. As of July 9, 2025, 36 patients received JNJ-5322 at the RP2D with a median follow-up of 14.4 months. At baseline, 26.5% (9/34) had high-risk cytogenetics, 13.9% had ISS stage III disease, and 8.3% had extramedullary disease. Patients received a median of 4 (range 2–11) prior lines of therapy; 75.0% were BCMA/GPRC5D naive and 52.8% were triple-class refractory. The most common nonhematologic TEAEs were infections (80.6% [gr 3, 33.3%]) and skin-related (66.7%, all gr 1/2) and nail-related (61.1%, majority [58.3%] gr 1) TEAEs. The most common hematologic TEAEs were lymphopenia (47.2% [gr 3/4, 44.4%]) and neutropenia (44.4% [gr 3/4, 33.3%]). The cumulative incidence of gr ≥3 infections plateaued within the first year of therapy. Intravenous immunoglobulin (IVIg) use was recommended to maintain Ig levels ≥400 mg/dL; 91.7% of patients received IVIg. Hypogammaglobulinemia was reported in 52.8% of patients; among these, 94.7% received IVIg. CRS occurred in 52.8% (gr 1, 41.7%; gr 2, 11.1%). In cohorts without (received 100 mg Q4W) and with (received 100 mg Q4W/Q8W) prophylactic tocilizumab, CRS occurred in 69.2% (gr 2, 15.4%) and 20.0% (gr 2, 0%), respectively. No ICANS events were reported. Taste changes occurred in 58.3% (gr 1, 41.7%; gr 2, 16.7%); median duration was 57 days. Of 36 patients who received the RP2D, 27 were BCMA/GPRC5D naive with a median follow-up of 15.0 months; these patients showed a high ORR of 100.0% with deepening of response (complete response or better [≥CR], 77.8%) and a 12-month progression-free survival rate of 96.3%. Apart from 1 patient who died while in very good partial response (due to pneumonia in the setting of hypogammaglobulinemia <200 mg/dL), all 26 patients remain in response at 15.0 months of median follow-up, demonstrating durable responses. MRD negativity at 10–5 was achieved in 100.0% (10/10) of evaluable patients. Updated analyses with 6 additional months of follow-up will be presented at the conference. With longer follow-up in part 1 of the phase 1 trial, JNJ-5322 continues to demonstrate responses comparable to CAR-T therapy (ORR 100.0%) that are durable and continue to deepen (≥CR 77.8%), with a safety profile similar or improved compared with BsAbs targeting BCMA or GPRC5D. JNJ-5322 offers off-the-shelf, Q4W dosing and 1 SUD with low rates of gr 2 CRS that may enable an efficient approach to dual antigen targeting via convenient administration and outpatient treatment. These findings support further evaluation of JNJ-5322 in patients with RRMM.

The UKMRA RADAR study is a phase II/III clinical trial for newly diagnosed multiple myeloma patients eligible for autologous stem cell transplant. It offers a risk-adapted approach with the addition of isatuximab for genetically high-risk patients, evaluated using local cytogenetics laboratories rather than centralised testing. We have observed excellent overall success rates, with > 90% patients assigned to a risk-adapted pathway following cytogenetic testing in 25 local laboratories nationwide, with clinically-relevant turnaround times allowing > 70% patients to commence isatuximab at the earliest opportunity if indicated. This paves the way for providing standard-of-care risk-adapted treatment for multiple myeloma patients in the UK.

Since the publication in 2021 of the European Hematology Association (EHA) Clinical Practice Guidelines for the treatment of patients with smouldering multiple myeloma (SMM) and multiple myeloma (MM), developed in collaboration with the European Society for Medical Oncology, a novel international staging system (R2-ISS) has been developed, several prognostic factors are entering clinical practice (such as minimal residual disease, circulating plasma cells and monoclonal protein assessed by mass spectrometry) and, at the time of writing, 14 novel regimens have been approved by the EMA and/or the FDA for the treatment of patients with MM. A multidisciplinary group of experts from the EHA and European Myeloma Network, based in various institutions mostly located in Europe, have updated the previous guidelines and produced algorithms for everyday clinical practice that incorporate levels of evidence and grades of recommendation based on the aforementioned new data. In these Evidence-Based Guidelines, we provide key treatment recommendations for both patients with newly diagnosed MM and those with relapsed and/or refractory MM, including guidance for the use of established drugs as well as contemporary immunotherapies. Novel approaches for the management of patients with SMM focus on those who might require early intervention. Finally, we provide recommendations for myeloma-related complications and adverse events, such as bone disease, renal impairment and infections, as well as for those associated with T cell-mobilizing therapies, such as cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome. In these Evidence-Based Guidelines, a multidisciplinary panel of experts from the European Hematology Association and the European Myeloma Network provide key treatment recommendations for patients with smouldering multiple myeloma, and newly diagnosed or relapsed and/or refractory multiple myeloma, addressing the use of established drugs and novel immunotherapies as well as the management of disease-specific and treatment-related complications and adverse events.

Belantamab Mafodotin (Belamaf) is a BCMA targeted antibody drug conjugate with a multi-modal mechanism of action including direct MMAF induced cellular cytotoxicity as well as immunogenic cell death. Belamaf in combination with bortezomib and dexamethasone (BVd) demonstrated superior progression-free and overall survival for patients with relapsed or refractory multiple myeloma (RRMM) compared to daratumumab, bortezomib and dexamethasone (DREAMM-7 trial) leading to regulatory approvals. However, the mean Belamaf compliance when dosed Q3W in DREAMM-7 was 51%, decreasing as treatment progressed (77% 0-6m, 68% 6-12m, 28% >12m) suggesting that further optimisation of the schedule is possible. Ocular adverse events with Belamaf mean eye examinations are recommended prior to dosing, adding to the treatment burden for patients and placing additional demands on healthcare resources. The Ocular Surface Disease Index (OSDI), a patient questionnaire, was retrospectively evaluated in the DREAMM-2 trial as a potential surrogate for ocular examinations. Notably, a negative questionnaire was able to rule out grade 3-4 keratopathy in 93.5% of examinations (Popat et al., ASH 2021). This questionnaire was adjusted to a 9-item Visual Related Anamnestic Tool (VRAT) to assess eye symptoms and vision related function. This can be used by healthcare professionals to evaluate ocular side-effects associated with Belamaf, potentially streamlining monitoring and improving patient experience. ProMMise is phase I/II muti-centre platform trial investigating Belamaf combinations for patients with RRMM after 1-3 prior lines of therapy. The ProMMise D arm will be conducted in two stages, with a primary objective of determining if BVd can be safely given using the VRAT without the need for mandated eye examinations. Secondary objectives include: to assess the agreement between the VRAT and eye care specialist-led dosing, and to assess treatment compliance and efficacy using a less intensive dosing schedule without eye assessments. In stage 1, 40 patients will have eye assessments prior to the first 3 doses as well as completing the VRAT. Dosing will be interrupted for ≥ grade 3 events or a positive VRAT. A safety assessment for the use of the VRAT will be performed following this by an independent Safety Review Committee. Thereafter, Stage 2 will enrol 60 patients with no mandated on-treatment eye assessments and ocular adverse events assessed using the VRAT alone prior to each Belamaf dose. If the questionnaire is positive, treatment will be interrupted. A multiple outcome Bayesian monitoring strategy will be used to monitor ocular toxicity in the short-term for participant safety and in the longer-term to assess the suitability of this approach. Patients will receive BVd in a less intensive schedule to DREAMM-7 based on the trial post-hoc analysis of actual treatment received to improve Belamaf compliance. A weekly bortezomib schedule is used in line with real world practice to reduce peripheral neuropathy, with home administration permissible for patient convenience. The ProMMise D schedule being evaluated is: Belamaf 2.5mg/kg for cycle 1 then 1.9mg/kg Q8W with bortezomib 1.3mg/m2 s.c. and 40mg dexamethasone weekly for 6 months. Following that, Belamaf monotherapy maintenance will commence Q12W until disease progression or intolerance. ProMMise D gained regulatory approval in December 2024. Enrolment is ongoing with results from Stage 1 expected in the first half of 2026. The ProMMise D trial aims to investigate a patient-centred approach to delivering Belamaf with bortezomib and dexamethasone with less intensive dosing to improve compliance and replacing ocular examinations with a simple questionnaire (VRAT). GSK provided funding and Belamaf supply. This study was also supported by Myeloma UK through the UKMRA-MUK- concept and access research programme. Trial registration number: ISRCTN19869915