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.

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.

Introduction: Talquetamab (Tal) is the first G protein–coupled receptor class C group 5 member D (GPRC5D) × CD3 bispecific antibody (BsAb) approved for treatment of patients with relapsed/refractory multiple myeloma (RRMM). Pomalidomide (Pom) is an established immunomodulatory drug with direct on-tumor apoptotic activity. Initial results of the phase 1b MonumenTAL-2 study (NCT05050097) combining Tal and Pom showed rapid and deep responses in patients (pts) with RRMM, with a safety profile consistent with the individual agents. We report updated safety and efficacy results of Tal + Pom from MonumenTAL-2 with longer follow-up (~2 years). Methods: Pts had ≥2 prior lines of therapy (LOT), including a proteasome inhibitor and lenalidomide. Prior exposure to BsAbs, chimeric antigen receptor (CAR)-T cell therapy, and Pom was permitted. Pts received subcutaneous Tal 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W), with step-up dosing, plus oral Pom 2 mg daily (days 1−21 of each 28-day cycle) starting in cycle 2 (increase to 4 mg permitted as of cycle 3). Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded by ASTCT criteria; all other AEs were graded by CTCAE v5.0. Response was assessed by investigators using IMWG 2016 criteria. Results: As of March 31, 2025, 35 pts were enrolled (n=16 QW and n=19 Q2W), with a median follow-up of 20.7 mo; relative dose intensity of Tal QW and Q2W was similar with longer follow-up. Twelve (34.3%) pts remain on treatment. Baseline characteristics were as previously reported. Briefly, median age was 65 years, median prior LOT was 3, 45.0% (9/20) had high-risk cytogenetics, and 20.0% had extramedullary disease. Prior treatment exposure included Pom (22.9%), BCMA CAR-T (8.6%), and BsAbs (2.9%); 65.7% were refractory to daratumumab. Efficacy outcomes were consistent with previous results: ORR was 85.7% (≥CR, 45.7%) and median duration of response (DOR) was not reached (12.5–NE) (12-mo DOR rate, 71.1%). Median progression-free survival (PFS) was 25.8 mo (12.9–NE) (12-mo PFS rate, 72.6%). High ORRs were observed in pts with prior exposure to CAR-T (100.0%, 3/3) or Pom (100.0%, 8/8). The safety profile was comparable with previously reported data and consistent with longer treatment duration. Common AEs were taste-related events (85.7%; grade [gr] 1, 40.0%, gr 2, 45.7%), infections (85.7%; gr 3/4, 31.4%), and CRS (74.3%; gr 3/4, 2.9%); neutropenia (68.6%), anemia (42.9%), and thrombocytopenia (31.4%) remained the most common hematologic AEs. CRS primarily occurred during step-up and cycle 1 doses, with no additional effect of Pom at cycle 2. ICANS occurred in 3 pts (all gr 1). Skin and nail GPRC5D-related AEs occurred in 74.3% (gr 3/4, 5.7%) and 68.6% (gr 3/4, 0%) of pts, respectively; no pts discontinued treatment due to these AEs. Weight loss occurred in 25.7% of pts (gr 3/4, 5.7%) and recovered in 66.7% at the time of data cutoff. No further discontinuations of any study treatment due to AEs were observed with longer follow-up vs the initial report (3 pts, 8.6%), indicating the absence of cumulative toxicity. AEs led to dose reduction of Tal or Pom in 25.7% and 48.6% of pts, respectively, to dose omissions in 65.7% and 80.0%, and to dose delays in 77.1% and 22.9%. With longer follow-up, fewer dose reductions of Tal were observed. In translational analyses, enhanced production of interferon (IFN)-γ and tumor necrosis factor was observed following addition of Pom, aligned with the mechanism of action of Pom and supporting preclinical data. Responding pts showed a trend toward higher induction of IFN-γ and markers associated with CD8+ T-cell activation compared with non-responding pts. Conclusions: With longer follow up, Tal + Pom continued to show high, deep, and durable responses in pts with RRMM. The safety profile remained consistent with early treatment, with few additional dose modifications or discontinuations observed in later cycles, highlighting the long-term tolerability of this regimen. These findings support the rationale for the phase 3 MonumenTAL-6 study (NCT06208150), which compares the efficacy of Tal + Pom vs investigator's choice of elotuzumab + Pom + dexamethasone or Pom + bortezomib + dexamethasone in pts with RRMM with 1–4 prior LOT.

Thrombocytosis is a commonly seen haematological abnormality. However, extreme thrombocytosis (EXT, defined as a platelet count of >1000 x 109/L) is a rare entity. It can be categorised as either primary (clonal) or secondary (reactive). There are little data on the incidence and management of secondary EXT in patients with underlying (non-myeloproliferative) malignancy. We retrospectively investigated the incidence, management and complications of EXT in patients at the Royal Marsden Hospital with underlying malignant diagnoses over a 12-year period. We identified 198 patients as having EXT during the study period; the majority (113, 57%) were female and the median age at diagnosis of malignancy was 55 years (range 1-86). Median follow-up was 55 months (range 0-177). The median highest platelet count reported in this patient population was 1112 x 109/L (range 1001 – 2593). The majority of patients had non-haematological malignancies (153, 77%). Of these, the most common diagnoses were lung cancer and mesothelioma (39, 25%) although a further 41 malignancies were seen. Myeloproliferative Neoplasm (MPN) screening for JAK2, CALR, MPL and BCR-ABL abnormalities was only done in 11 patients (5.5%); none were positive. The majority of patients in this cohort (70%) had complete resolution of thrombocytosis, but 56 (28%) had persistently elevated platelet counts. Antiplatelet therapy was documented in 32 patients (16%), although it was a pre-existing medication in 11 patients (34.5%). Indications for commencing antiplatelets included a new thrombotic event (CVA or MI) in six patients (18%), and for thrombocytosis itself in 11 patients (34.5%). In the remaining patients (13%) the reason for antiplatelet therapy was not documented. Therapeutic anticoagulation was commenced in 36 patients (18%). In the majority of cases, the indication for anticoagulation was thrombosis (35, 97.3%). Only one patient (2.7%) was started on therapeutic anticoagulation due solely to thrombocytosis. In this patient population, 42 patients (21%) had a diagnosed thrombotic event, of which the majority (35, 83%) were venous. Pulmonary embolism (PE) was the most common event, seen in 13 patients (31%). Twenty-five patients (59.5%) had thrombocytosis at the time of thrombosis. In terms of management of thrombosis, six of the patients with arterial thrombosis were treated with antiplatelet therapy. As outlined above, the majority of patients who had a venous thrombotic event were managed with therapeutic anticoagulation. The rate of thrombotic events in this study is higher than in the published literature, which generally quotes a rate of thrombosis in cancer patients as 4-6% (Khamis et al 2025, Bleeker et al 2011). Within this patient population a paediatric subgroup was analysed; 44 patients with EXT under the age of 18 were identified, with a median platelet count of 1147x109/L (range 1001 – 1781). None of the paediatric population received aspirin or anticoagulation as thromboprophylaxis, and 4 patients (9%) had thrombotic complications. Almost two thirds of patients had died at the time of data collection (128, 64.5%). The most common cause of death was progressive malignancy (84, 66%). Infection was the cause of death in 7 patients (5.5%), and 35 patients (27%) were lost to follow up and cause of death was unknown. Only 2 patients (1.5%) had a documented thrombotic cause of death (both CVA). The median overall survival from identification of thrombocytosis in this cohort of patients was 26 months (range 0 – 117). This study analysed a large cohort of patients with non-MPN malignancy who developed EXT. MPN screening is rarely undertaken in these patients despite persistence of the elevated platelet count in many cases. EXT may contribute to the risk of thrombotic complications in patients with malignancy. Given the high rate of thrombotic complications in this cohort, we suggest that patients with EXT in the setting of malignancy should be referred to the specialist Haematology team for consideration of further investigation including screening for MPN, especially if the thrombocytosis is persistent. This data would also support a change in practice to consider thromboprophylaxis in patients with underlying malignancy and EXT. This real-world data has shown that thrombotic complications occurred in a higher proportion of these patients than expected, and therefore further studies are required to identify the optimal management of these patients.

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.

Abstract Background Data on sensitivity and cost effectiveness has shaped national and International Myeloma Working Group guidelines to include non-invasive whole-body MRI (WBMRI) for Multiple Myeloma (MM) diagnosis and follow up. Furthermore, acquisition has been standardised (MY-RADS) in line with other oncological WBMRI protocols. This presents an opportunity to complement accurate disease detection and response assessments with body composition metrics beyond traditional measures such as BMI and sarcopaenia. The aim of this study was to define the technical capability of AI to derive quantitative image-derived phenotypes (IDPs) in non-diseased tissue from WBMRI in patients with MM and to derive longitudinal measurements and exploratory associations with imaging response. Methods An AI-based segmentation algorithm was trained to quantify the volume of skeletal muscle, abdominal subcutaneous adipose tissue (ASAT) and visceral adipose tissue (VAT), internal organs, bones and relative fat fraction (rFF) of the liver. The model (originally trained on >100 UK Biobank WBMRIs) was optimised for patients with MM using WBMRI scans from 20 MM patients. The resulting pipeline was applied to WBMRI scans from 69 MM patients with active MM who had been recruited to the iTiMM study (NCT02403102) and imaged at 3 time points: (1) baseline, (2) post-induction chemotherapy, and (3) post-autologous stem cell transplant (ASCT). Changes in IDPs between time points were performed using paired univariate hypothesis tests. MY-RADS response assessment categories (RAC score 1 (best response) vs 2 or greater), were used to evaluate associations between IDPs and radiological response. Volumetric IDPs were divided by height squared to minimize variability due to patient size. Associations between IDPs and MY-RADS RAC score were measured with logistic regression models, selected using a penalized model selection criterion, that included both clinical measurements and IDPs. Results The segmentation model achieved very high performance, with the average Dice score across all structures being 0.916 [range 0.812-0.99]. Longitudinal analysis revealed changes in normalised IDPs following therapy, where skeletal muscle and cardiac volume decreased and ASAT and VAT increased between the baseline WBMRI and the post-induction WBMRI. ASAT and VAT then decreased between the post-induction WBMRI and the post-ASCT WBMRI falling to below baseline. Liver rFF increased between the baseline WBMRI and the post-induction WBMRI but did not change thereafter. BMI increased on average between the baseline and post-induction WBMRI and decreased between the post-induction WBMRI and the post-ASCT WBMRI. A regression model using baseline age, total disease burden score, skeletal muscle, ASAT, VAT, and kidney volume was associated with MY-RADS RAC score on the post-ASCT WBMRI. More VAT at baseline was associated with an excellent MY-RADS RAC score of 1 post-ASCT. Increased skeletal muscle, ASAT, and age at baseline were associated with an inferior MY-RADS RAC score of 2 or greater. Conclusions To our knowledge this is the first study of AI derived body composition metrics using standard WBMRI data in patients with multiple myeloma. The AI-based IDP pipeline has been successfully trained for WBMRI in MM patients, overcoming the challenges posed by skeletal deformities and abnormal bone marrow signal. This study demonstrated significant tissue-specific changes over time, including a reduction in skeletal muscle and increases in ASAT, VAT and liver rFF following induction chemotherapy which we note correspond with the period of high dose steroid therapy. Higher VAT at baseline was also associated with best imaging response on the post ASCT WBMRI. These associations suggest potential links between body composition dynamics and radiological treatment response and could be in line with the obesity paradox, where greater adiposity is sometimes associated with improved outcome. However, weight dependent dosing of bortezomib and melphalan may also contribute. The ability to apply AI to routine WBMRI scans offers an objective and scalable approach to monitor tissue-specific changes during treatment and to amplify the impact of AI-derived metrics of disease burden and skeletal deformity also under development. This study highlights the potential of IDPs and their role towards a more holistic view of the patient and non invasive insights into body composition, wellness and toxicity.

Minimal residual disease (MRD) testing has underpinned the evaluation and expansion of therapeutic options for patients with multiple myeloma (MM). Imaging is essential for evaluating residual disease status, overcoming sampling errors inherent with other MRD modalities. The accuracy of whole-body MRI (WB-MRI) has led to its incorporation into MM diagnostic imaging guidelines. We report here on the prospective iTIMM trial (image-guided theranostics in MM; NCT02403102), designed to evaluate imaging residual disease using contemporary, functional WB-MRI as per MY-RADS protocol. In iTIMM, 70 MM patients planned to undergo autologous stem cell transplantation ASCT in newly diagnosed MM or at first relapse, underwent WB-MRI before start of induction and at day 100 post-ASCT. Patients with residual disease post-ASCT (RAC2 or higher) had shorter progression-free survival (median 24 months, 95% confidence interval (CI): 19-41 vs. 42 months, 95% CI: 37-not evaluable (NE), log-rank p = 0.013; hazard ratio (HR) 2.09 (95% CI: 1.15-3.78) and overall survival (median 47 months, 95% CI: 30.9-NE vs. NE (95% CI: NE-NE), p = 0.002, HR = 5.45 (95% CI: 1.67-17.87) than those without (RAC1). Imaging response also refined the prognostic association of bone marrow MRD and serological response. Our results support WB-MRI implementation for evaluation of residual disease alongside conventional laboratory-based assessments.

Introduction:Multiple myeloma (MM) is diagnosed in 6,000 people in the UK yearly. A performance status measure, based on the patients' reported level of physical activity, is used to assess patients' fitness for treatment. This systematic review aims to explore the current evidence for the acceptability of using wearable devices in patients treated for MM to measure physical activity directly. Methods:Three databases were searched (MEDLINE, EMBASE and CINAHL) up until 7th September 2023. Prospective studies using wearable devices to monitor physical activity in patients on treatment for MM were included. Bias across the studies was assessed using the CASP tool. Results:Nine studies, with 220 patients on treatment for MM, were included. Only two studies had a low risk of bias. Different wearable device brands were used for varying lengths of time and were worn on either the wrist, upper arm, or chest. Adherence, reported in seven studies, ranged from 50% to 90%. Six studies reported an adherence greater than 75%. Although physical activity was also measured in a heterogenous manner, most studies reported reduced physical activity during treatment, associated with a higher symptom burden. Conclusion:Monitoring patients receiving treatment for MM with a wearable device appears acceptable as an objective measure to evaluate physical activity. Due to the heterogeneity of the methods used, the generalisability of the results is limited. Future studies should explore the data collected prospectively and their ability to predict relevant clinical outcomes.