Abstract Introduction: In RRMM, increasing rates of pt attrition and decreasing durability of responses with each line of therapy (LOT) necessitate early treatment (tx) with the most effective therapies. Immunotherapies that are widely accessible across different MM tx settings have the potential to change the trajectory of RRMM. Teclistamab (Tec), the first approved BCMA×CD3 bispecific antibody (BsAb) for heavily pretreated RRMM, provided deep, durable responses in MajesTEC-1, with improved efficacy and safety in earlier LOTs. Daratumumab (Dara), a standard-of-care (SoC) foundational CD38 targeted therapy with direct on-tumor activity, has been shown to deplete immunosuppressive T-cells and expand cytotoxic T-cells, creating an immune-permissive microenvironment for synergistic Tec-mediated killing of MM cells. MajesTEC-3 (NCT05083169) evaluates Tec-Dara vs SoC DPd/DVd in RRMM. We report initial results for this first phase 3 study of BsAb therapy in MM. Methods: Eligible pts had 1-3 prior LOTs including a PI and lenalidomide (Len; pts with 1 prior LOT must have been Len-refractory) with progressive disease (PD) on or after the last LOT. Pts with prior BCMA-directed therapy or refractory to anti-CD38 were excluded; prior anti-CD38 exposure was permitted. Pts were randomized 1:1 to Tec-Dara or DPd/DVd. The Tec-Dara group received 28-day cycles (C) of Tec (1.5 mg/kg QW in C1-2 [C1 preceded by the approved step-up dose schedule]; 3 mg/kg Q2W in C3-6; and 3 mg/kg Q4W in C7+) with Dara; steroids were not required after C1 Day 8. Tec and Dara dosing were aligned with the approved Dara schedule. DPd/DVd were administered per approved schedules. Progression-free survival (PFS) by IRC was the primary endpoint; secondary endpoints included complete response or better (≥CR), overall response, minimal residual disease (MRD) negativity (10–5; next-generation sequencing), overall survival (OS), time to worsening of symptoms (MySIm-Q), and safety. Results: 587 pts were randomized (Tec-Dara, n=291; DPd/DVd, n=296). Median (range) age was 64 (25-88) yrs, median number of prior LOTs was 2 (1-3). With 34.5-mo median follow-up, Tec-Dara significantly improved PFS vs DPd/DVd (HR, 0.17; 95% CI, 0.12-0.23; P<0.0001); mPFS was NR and 18.1 mo, and 36-mo PFS rate was 83.4% and 29.7%, respectively. PFS benefit was consistent across all prespecified and clinically relevant pt subgroups, including age ≥75 yrs, Len-refractory, high-risk cytogenetics, ≥60% bone marrow plasma cells, soft-tissue plasmacytomas, and anti-CD38 exposed. Significantly higher rates of ≥CR (81.8% vs 32.1%; OR, 9.56; 95% CI, 6.47-14.14), overall response (89.0% vs 75.3%; OR, 2.65; 95% CI, 1.68-4.18), and MRD-negativity (58.4% vs 17.1%; OR, 6.78; 95% CI, 4.53-10.15) were observed with Tec-Dara (P<0.0001). There were 45 deaths with Tec-Dara and 96 with DPd/DVd, primarily due to PD (4.6%; 20.3%). OS significantly favored Tec-Dara (HR, 0.46; 95% CI, 0.32-0.65; P<0.0001), including across all prespecified subgroups. The 36-mo OS rates were 83.3% and 65.0%, respectively and >90% of Tec-Dara pts alive at 6 mo were also alive at 30 mo. Median time to worsening of MM symptoms was NR with Tec-Dara vs 39.9 mo with DPd/DVd (HR, 0.50; 95% CI, 0.34-0.72; P=0.0002). At data cutoff, 49.4% of pts remained on study tx (Tec-Dara, 71.0%; DPd/DVd, 28.3%). Median tx duration was twice as long with Tec-Dara vs DPd/DVd (32.4 vs 16.1 mo). Frequency of grade 3/4 (Tec-Dara, 95.1%; DPd/DVd, 96.6%) and grade 5 (7.8%; 6.2%) treatment-emergent adverse events (TEAEs), were comparable (safety set: Tec-Dara, n=283; DPd/DVd, n=290). Serious TEAEs occurred in 70.7% Tec-Dara and 62.4% DPd/DVd pts; tx discontinuations due to TEAEs were low (4.6% vs 5.5%). Any grade infections occurred in 96.5% and 84.1% of Tec-Dara and DPd/DVd pts, respectively; grade 3/4 infections occurred in 54.1% and 43.4%. New onset grade ≥3 infections decreased over time, coinciding with transition to Q4W dosing and supported by antimicrobial and Ig prophylaxis guidance. CRS rate was 60.1% (grade 1/2: 44.2%/15.9%) and ICANS was 1.1% with Tec-Dara. Conclusion: We demonstrate the clinically remarkable and statistically significant PFS and OS benefits of Tec-Dara vs SoC triplets in RRMM, with 83.4% of Tec-Dara pts alive and progression-free at 3 yrs. Infections with Tec-Dara were well managed with established protocols. This highly effective, off-the-shelf, immunotherapy combination represents a new SoC for RRMM as early as first relapse.

Abstract Background The Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q) is a validated, disease-specific patient-reported outcome (PRO) instrument that measures symptoms and impacts experienced by patients with multiple myeloma (MM). We describe key measurement properties of the MySIm-Q instrument using CARTITUDE-4 data. Methodology The phase 3 CARTITUDE-4 (NCT04181827) trial compares ciltacabtagene autoleucel with standard-of-care regimens in patients with lenalidomide-refractory MM after 1–3 lines of therapy. Following US Food and Drug Administration guidance on the use of PRO measures in clinical trials, the reliability, as well as aspects of construct validity, convergent and discriminant validity of the MySIm-Q symptom and impact scores (2 separate concepts) were assessed. Results In total, 361 patients completed MySIm-Q assessments. Internal consistency results met the predefined threshold (McDonald’s ꞷ coefficient > 0.7; ꞷ=0.87 for total symptom scores, ꞷ=0.79 for total impact scores), while test-retest reliability was slightly below this threshold (intraclass correlation coefficient [ICC](2,1) > 0.70; ICC = 0.67 and 0.65, respectively). Known-groups validity of total symptom and total impact scores was established through multiple hypotheses. Factor scores estimated from the confirmatory factor analysis model were highly correlated with simple observed scores calculated in symptom and impact scores. Item-level convergent and discriminant validity was supported for all and nearly all items, respectively. Domain convergent and discriminant validity for total scores were largely met. Conclusions These results demonstrate that the MySIm-Q yields reliable and valid scores based on a number of evidentiary sources, supporting its use as a fit-for-purpose PRO instrument in clinical outcome assessments for patients with MM. Trial registration CARTITUDE-4: ClinicalTrials.gov ID: NCT04181827. Date of registration: 27 November 2019. URL: https://www.clinicaltrials.gov/study/NCT04181827 .

Background In CARTITUDE-4, ciltacabtagene autoleucel (cilta-cel) significantly improved progression-free survival (primary endpoint; previously reported) versus standard of care in patients with relapsed, lenalidomide-refractory multiple myeloma. We report here patient-reported outcomes. Methods In the ongoing, phase 3, open-label CARTITUDE-4 study, patients were recruited from 81 sites in the USA, Europe, Asia, and Australia, and were randomly assigned 1:1 to cilta-cel (target, 0 center dot 75 x 10(6) CAR-T cells/kg) or standard of care (daratumumab, pomalidomide, and dexamethasone; pomalidomide, bortezomib, and dexamethasone). Eligible patients had relapsed, lenalidomide-refractory multiple myeloma, received one to three previous treatment lines including a proteasome inhibitor and an immunomodulatory drug, and had an ECOG performance status of 0 or 1. Secondary endpoints reported here include time to sustained worsening of symptoms (Multiple Myeloma Symptom and Impact Questionnaire [MySIm-Q]; a key secondary endpoint) and change in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire Core C30 (intention-to-treat population) and EuroQol 5-Dimension 5-Level (EQ-5D-5L; intention-to-treat population). This study is registered with ClinicalTrials.gov number NCT04181827 and is ongoing. Findings Patients were enrolled from July 10, 2020, to Nov 17, 2021, and 419 of 516 screened patients were randomly assigned (cilta-cel, n=208; standard of care, n=211; median follow-up, 15 center dot 9 months [IQR 12 center dot 4 to 17 center dot 8]); median age was 61 years. 191 (92%) of 208 patients in the cilta-cel group and 190 (91%) of 209 evaluable patients in the standardof-care group completed baseline assessments. MySIm-Q compliance post-baseline was 70 to 81% (cilta-cel) and 79 to 89% (standard of care). MySIm-Q median time to sustained symptom worsening with cilta-cel versus standard of care was 23 center dot 7 versus 18 center dot 9 months (HR 0 center dot 42; 95% CI 0 center dot 26 to 0 center dot 68). 12-month mean changes for EORTC global health status (GHS) were +10 center dot 1 (95% CI 7 center dot 0 to 13 center dot 1) and -1 center dot 5 (95% CI -5 center dot 3 to 2 center dot 3) points and were +8 center dot 0 (95% CI 5 center dot 2 to 10 center dot 7) and +1 center dot 4 (95% CI -1 center dot 9 to 4 center dot 7) points for EQ-5D-5L visual analogue scale (VAS). Rates of clinically meaningful improvements in GHS and VAS were higher with cilta-cel than with standard of care. Interpretation Health-related QoL improvements and delayed symptom worsening support cilta-cel's clinical efficacy in lenalidomide-refractory disease. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Background In CARTITUDE-4, ciltacabtagene autoleucel (cilta-cel) significantly improved progression-free survival (primary endpoint; previously reported) versus standard of care in patients with relapsed, lenalidomide-refractory multiple myeloma. We report here patient-reported outcomes. Methods In the ongoing, phase 3, open-label CARTITUDE-4 study, patients were recruited from 81 sites in the USA, Europe, Asia, and Australia, and were randomly assigned 1:1 to cilta-cel (target, 0·75 × 106 CAR-T cells/kg) or standard of care (daratumumab, pomalidomide, and dexamethasone; pomalidomide, bortezomib, and dexamethasone). Eligible patients had relapsed, lenalidomide-refractory multiple myeloma, received one to three previous treatment lines including a proteasome inhibitor and an immunomodulatory drug, and had an ECOG performance status of 0 or 1. Secondary endpoints reported here include time to sustained worsening of symptoms (Multiple Myeloma Symptom and Impact Questionnaire [MySIm-Q]; a key secondary endpoint) and change in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire Core C30 (intention-to-treat population) and EuroQol 5-Dimension 5-Level (EQ-5D-5L; intention-to-treat population). This study is registered with ClinicalTrials.gov number NCT04181827 and is ongoing. Findings Patients were enrolled from July 10, 2020, to Nov 17, 2021, and 419 of 516 screened patients were randomly assigned (cilta-cel, n=208; standard of care, n=211; median follow-up, 15·9 months [IQR 12·4 to 17·8]); median age was 61 years. 191 (92%) of 208 patients in the cilta-cel group and 190 (91%) of 209 evaluable patients in the standard- of-care group completed baseline assessments. MySIm-Q compliance post-baseline was 70 to 81% (cilta-cel) and 79 to 89% (standard of care). MySIm-Q median time to sustained symptom worsening with cilta-cel versus standard of care was 23·7 versus 18·9 months (HR 0·42; 95% CI 0·26 to 0·68). 12-month mean changes for EORTC global health status (GHS) were +10·1 (95% CI 7·0 to 13·1) and –1·5 (95% CI –5·3 to 2·3) points and were +8·0 (95% CI 5·2 to 10·7) and +1·4 (95% CI –1·9 to 4·7) points for EQ-5D-5L visual analogue scale (VAS). Rates of clinically meaningful improvements in GHS and VAS were higher with cilta-cel than with standard of care. Interpretation Health-related QoL improvements and delayed symptom worsening support cilta-cel's clinical efficacy in lenalidomide-refractory disease. Funding Janssen Research & Development, Legend Biotech USA.

Background Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved. Methods In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria. Results Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified. Conclusions Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.) Daratumumab for High-Risk Smoldering Multiple Myeloma Among patients with smoldering multiple myeloma at high risk for progression, progression-free survival at 5 years was 63.1% with daratumumab monotherapy, as compared with 40.8% with active monitoring.

Introduction: High-risk smoldering multiple myeloma (SMM) is an asymptomatic precursor disorder to active multiple myeloma (MM) without approved treatment options. However, recent evidence suggests patients at high risk of progression to MM may benefit from early treatment. Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with direct on-tumor and immunomodulatory mechanisms of action. DARA is approved as monotherapy for relapsed/refractory MM (RRMM) and in combination with standard-of-care regimens for RRMM and newly diagnosed MM. Based on the encouraging activity and tolerability observed with DARA monotherapy in patients with intermediate- or high-risk SMM in the phase 2 CENTAURUS study, the phase 3 AQUILA study sought to determine if DARA could delay progression to MM versus active monitoring. Here we report the primary analysis from the AQUILA study. Methods: Eligible patients had a confirmed diagnosis of high-risk SMM for ≤5 years, defined as clonal bone marrow plasma cells (BMPCs) ≥10% and ≥1 risk factor (serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 and <100, and/or clonal BMPCs >50% to <60%). Focal and lytic lesion assessment was performed in screening by CT and MRI and centrally reviewed prior to study enrollment. Patients were randomized 1:1 to receive DARA SC versus active monitoring. DARA (QW in Cycles 1 and 2, Q2W in Cycles 3-6, and Q4W thereafter) was given in 28-day cycles until cycle 39, 36 months, or disease progression, whichever came first. The primary endpoint was progression-free survival (PFS), defined as progression to active MM as assessed by an independent review committee and according to IMWG diagnostic criteria for MM (SLiM-CRAB) or death. Major secondary endpoints included overall response rate (ORR), PFS on first-line MM treatment (PFS2), and overall survival (OS). Results: A total of 390 patients (DARA, n = 194; active monitoring, n = 196) were randomized. Median (range) age (64 [31-86] years) and time from initial SMM diagnosis to randomization (0.72 [0-5.0] years) were balanced between treatment groups. Median treatment duration in the DARA group was 38 cycles (35.0 months). At a median (range) follow-up of 65.2 (0-76.6) months, PFS was significantly improved with DARA versus active monitoring (HR, 0.49; 95% CI, 0.36-0.67; P <0.0001). Median PFS was not reached in the DARA group versus 41.5 months for active monitoring; estimated 60-month PFS rates were 63.1% versus 40.8%, respectively. Prespecified analyses showed generally consistent PFS improvement with DARA versus active monitoring across subgroups. ORR was 63.4% with DARA versus 2.0% with active monitoring (P <0.0001). As of the clinical cutoff, 64 (33.0%) patients in the DARA group and 102 (52.0%) patients in the active monitoring group had started first-line MM treatment. Median time from randomization to the date of first-line MM treatment was not reached with DARA versus 50.2 months with active monitoring (HR, 0.46; 95% CI, 0.33-0.62; nominal P <0.0001). There was a positive trend in favor of DARA for PFS2 (HR, 0.58; 95% CI, 0.35-0.96) and OS (60-month OS rates: DARA, 93.0%; active monitoring, 86.9%; HR, 0.52; 95% CI, 0.27-0.98). A total of 41 deaths were observed, 15 for the DARA group and 26 for the active monitoring group. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 40.4% and 30.1% of patients in the DARA and active monitoring groups, respectively. The most common (≥5% in either group) grade 3/4 TEAE was hypertension (DARA, 5.7%; active monitoring, 4.6%). The frequency of TEAEs leading to DARA discontinuation was low (5.7%), as was the incidence of fatal TEAEs in both groups (DARA, 1.0%; active monitoring, 2.0%). Conclusions: DARA monotherapy was well tolerated and demonstrated a clinically meaningful and significant benefit in preventing or delaying progression to active MM compared with active monitoring in patients with high-risk SMM. ORR was significantly higher and time to first-line MM treatment was prolonged with DARA compared with active monitoring. This was accompanied by positive trends for PFS2 and OS in favor of DARA. These results strongly support the benefit of early intervention with DARA monotherapy versus active monitoring, the current standard of care, in patients with high-risk SMM.

BACKGROUND:In a phase 1-2 trial, teclistamab, a bispecific antibody targeting CD3 on T-cell surfaces and B-cell maturation antigen on myeloma cells, showed durable responses in heavily pretreated patients with relapsed or refractory multiple myeloma. Daratumumab, a monoclonal antibody targeting CD38 protein, has shown survival benefit in patients with multiple myeloma. METHODS:In this phase 3 trial, we randomly assigned patients with one to three previous lines of therapy to receive combination therapy with teclistamab-daratumumab or daratumumab combined with dexamethasone plus the investigator's choice of pomalidomide (DPd) or bortezomib (DVd) - the DPd or DVd group. The primary end point was progression-free survival, as assessed by an independent review committee. RESULTS:A total of 587 patients underwent randomization (291 to receive teclistamab-daratumumab and 296 to receive DPd or DVd). At a median of 34.5 months, progression-free survival was significantly longer with teclistamab-daratumumab than with DPd or DVd. The estimated 36-month progression-free survival was 83.4% in the teclistamab-daratumumab group and 29.7% in the DPd or DVd group (hazard ratio, 0.17; 95% confidence interval, 0.12 to 0.23; P<0.001). More patients in the teclistamab-daratumumab group than in the DPd or DVd group had a complete response or better (81.8% vs. 32.1%), an overall response (89.0% vs. 75.3%), and minimal residual disease negativity (10-5; 58.4% vs. 17.1%) (P<0.001 for all comparisons). Serious adverse events occurred in 70.7% of the patients in the teclistamab-daratumumab group and in 62.4% of those in the DPd or DVd group; death from adverse events occurred in 7.1% and 5.9%, respectively. CONCLUSIONS:In patients with multiple myeloma who had received one to three previous lines of therapy, those in the teclistamab-daratumumab group had significantly longer progression-free survival than those in the DPd or DVd group. (Funded by Johnson & Johnson; ClinicalTrials.gov number, NCT05083169.).

Background: Ciltacabtagene autoleucel (cilta-cel) demonstrated superior progression-free survival (PFS) and overall survival compared to standard of care (SOC; pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone) in patients with lenalidomide-refractory multiple myeloma (MM) after 1-3 prior lines of therapy (LOTs) in the phase 3 CARTITUDE-4 trial. A single cilta-cel infusion showed significant and clinically meaningful PFS vs. SOC (hazard ratio [HR]: 0.26 [protocol-specified weighted analysis]; P<0.0001) at a median follow-up of 15.9 months. A second interim analysis demonstrated a significant reduction in the risk of death by 45% (HR: 0.55; P=0.0009), compared to continuous SOC, with an estimated 30-month survival rate of 76.4%. To support these significant clinical benefits, here we report the patient reported outcomes (PROs) and time to next anti-myeloma therapy (TTNT) at ~3-year median follow-up. Methods: Eligible patients enrolled in CARTITUDE-4 included those with lenalidomide-refractory MM who received 1-3 prior LOTs including an immunomodulatory agent and a proteasome inhibitor. A total of 419 patients were randomized to receive either cilta-cel (N=208) or SOC (N=211). The Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q), including symptom (pain, fatigue, digestion, cognition) and impact (activity limitations, social functioning, emotional impact) domains, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), were administered to all patients until disease progression. Time to worsening (TTW) of symptoms and impact were defined as the time from randomization to a decrease in score of at least 0.5 standard deviation from baseline without an observed superior subsequent improvement, and TTW of global health status/quality of life (GHS/QoL) was defined using an anchor-based approach with CARTITUDE-4 data. TTNT was defined as time from randomization to the start of subsequent anti-myeloma therapy or death due to progressive disease. These outcomes were assessed using the Kaplan-Meier method. Cox proportional hazards models were used to estimate HRs and 95% confidence intervals (CIs). The clinical data cut-off of this analysis was May 1, 2024, with median follow-up of 34 months. Results: Based on the MySIm-Q symptom and impact domain scores, cilta-cel was associated with significantly longer TTW of symptoms (HR: 0.38; 95% CI: 0.24-0.61; P<0.0001) and impact (HR: 0.42; 95% CI: 0.26-0.70; P=0.0007), compared to SOC. By 30 months after randomization, 77% of patients treated with cilta-cel had not experienced worsening of symptoms, compared to 63% of patients on SOC. Similarly, 83% of patients on cilta-cel had not experienced worsening of functional impacts, compared to 69% of the SOC arm at 30 months. The median time until symptom worsening was not reached (NR) for cilta-cel, and was 34.33 (95% CI: 32.20-NR) months for SOC. A median time to impact worsening of 39.16 (95% CI: 38.70-NR) months was estimated for the cilta-cel arm, compared to 35.88 (95% CI: 32.20-NR) months for SOC. MySIm-Q results are further supported by those observed on the EORTC QLQ-C30 GHS/QoL scale, with time to worsening significantly delayed (HR: 0.40; 95% CI: 0.25-0.64; P<0.0001) for cilta-cel compared to SOC. For patients treated with cilta-cel, 79% had not experienced a worsening of GHS/QoL by 30 months, compared to 66% of patients on SOC. The median time to GHS/QoL worsening for cilta-cel was 39.92 (95% CI: 39.92-NR) months, compared to 34.33 (95% CI: 32.03-NR) months for SOC. Treatment with cilta-cel significantly delayed, by 66%, the time to subsequent anti-myeloma treatment or death due to progressive disease (HR: 0.34; 95% CI: 0.26-0.46; P<0.0001) compared to SOC. The median TTNT was not reached for the cilta-cel arm and was 13.37 (95% CI: 11.99-17.08) months for the SOC arm. Conclusion: The increase in the TTNT and sustained benefits in PROs, along with prolonged survival, support cilta-cel as a new SOC treatment for MM patients who are refractory to lenalidomide and have received 1-3 prior LOTs. Importantly, with ~3 years of follow-up, a single infusion of cilta-cel provided patients with a longer delay in worsening of MM related symptoms, functional impacts, and GHS/QoL. The totality of clinical and patient-reported evidence demonstrates the significant benefit of cilta-cel.

PURPOSE:Non-response (NR) to patient-reported outcome (PRO) questionnaires may cause bias if not handled appropriately. Collecting reasons for NR is recommended, but how reasons for NR are related to missing data mechanisms remains unexplored. We aimed to explore this relationship for intermittent NRs. METHODS:Patients with multiple myeloma completed validated PRO questionnaires at enrolment and 12 follow-up time-points. NR was defined as non-completion of a follow-up assessment within seven days, which triggered contact with the patient, recording the reason for missingness and an invitation to complete the questionnaire (denoted "salvage response"). Mean differences between salvage and previous on-time scores were estimated for groups defined by reasons for NR using linear regression with clustered standard errors. Statistically significant mean differences larger than minimal important difference thresholds were interpreted as "missing not at random" (MNAR) mechanism (i.e. assumed to be related to declining health), and the remainder interpreted as aligned with "missing completely at random" (MCAR) mechanism (i.e. assumed unrelated to changes in health). RESULTS:Most (7228/7534 (96%)) follow-up questionnaires were completed; 11% (802/7534) were salvage responses. Mean salvage scores were compared to previous on-time scores by reason: those due to hospital admission, mental or physical reasons were worse in 10/22 PRO domains; those due to technical difficulties/procedural errors were no different in 21/22 PRO domains; and those due to overlooked/forgotten or other/unspecified reasons were no different in any domains. CONCLUSION:Intermittent NRs due to hospital admission, mental or physical reasons were aligned with MNAR mechanism for nearly half of PRO domains, while intermittent NRs due to technical difficulties/procedural errors or other/unspecified reasons generally were aligned with MCAR mechanism.

Introduction: The phase 3 CARTITUDE-4 trial (NCT04181827) in patients with multiple myeloma (MM) after 1-3 lines of therapy compared ciltacabtagene autoleucel (cilta-cel) with standard of care (SOC; pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone). In the primary analysis, a single cilta-cel infusion significantly improved progression-free survival (hazard ratio [HR], 0.26; P<0.0001) and increased the rate and depth of response vs SOC. Here, we present adjusted comparisons of patient-reported outcomes (PROs) from patients randomized to cilta-cel vs SOC in CARTITUDE-4. Methods:419 patients with lenalidomide-refractory MM and 1-3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, were randomized (intent-to-treat [ITT] population) to receive cilta-cel (N=208) or SOC (N=211). European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30; 100-point scale), EuroQoL 5-Dimension 5-Level (EQ-5D-5L; 100-point scale), and Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q; 5-point scale) questionnaires were administered to all patients until disease progression. PRO compliance was calculated as the number of patients whose PROs were received divided by the number whose PROs were expected (ie, all patients on study pre disease progression and before subsequent therapy for each time point). Mixed-model for repeated measures analyses were performed on the ITT population to analyze changes from baseline for each arm and included the baseline PRO score and prognostic characteristics as covariates to balance arms and to adjust for confounders. Assessments after the start of subsequent therapy were excluded. Time to symptom worsening, defined as a clinically meaningful increase (≥0.5 standard deviation of pooled baseline values) without a subsequent reduction in MM symptoms, was assessed using the Kaplan-Meier method. Results: At clinical cut-off on November 1, 2022, 99 patients in the cilta-cel arm and 66 in the SOC arm had both baseline and 12-month PRO assessments, representing data prior to progression. PRO compliance was 100% at baseline and decreased with subsequent visits to 74% in the cilta-cel arm and 81% in the SOC arm at month 12. Patients reported improved functioning and symptom reduction from baseline in the cilta-cel arm, while PRO scores in the SOC arm trended towards worsening or lower degrees of improvement from baseline for most domains and symptoms. The average improvement from baseline to month 12 (least squares [LS] mean change) for patients who received cilta-cel exceeded clinically meaningful thresholds for global health status (10.1 points), pain (-10.2 points), and the visual analogue scale (8.0 points); improvements in fatigue (-9.1 points) and emotional functioning (9.5 points) neared clinically meaningful thresholds (Table). For all other EORTC QLQ-C30 domains, results numerically favored cilta-cel. On the MySIm-Q total symptom scale, the median time until MM symptom worsening in the cilta-cel arm was 23.7 months (95% CI, 22.1-not estimable) and was 18.9 months (95% CI, 16.8-not estimable) in the SOC arm (HR, 0.42). Conclusions:Patients with lenalidomide-refractory MM who had 1-3 prior lines of therapy demonstrated clinically meaningful improvements in health-related quality of life and meaningful reductions in disease-specific symptoms on multiple PRO endpoints after a single cilta-cel infusion. Improvements in health-related quality of life were numerically greater with cilta-cel than with continuously administered SOC treatments across all scales. With previously reported data showing that cilta-cel significantly improves PFS, response rate, and depth of response, these results strengthen the potential for cilta-cel to be a new SOC for patients with lenalidomide-refractory MM after first relapse.

BACKGROUND Bilateral carpal tunnel syndrome (CTS) is a common extracardiac manifestation of amytoidosis and usually predates overt cardiac amytoidosis (CA) by several years. Screening studies on patients undergoing CTS surgery have shown a low yield of CA (2.0%), but high prevalence of amytoid in the carpal ligament. The proportion of patients with amytoid in the carpal ligament who later develop CA is unknown. OBJECTIVES The authors sought to investigate the prevalence of undiagnosed CA 5 to 15 years after surgery for bilateral CTS. METHODS Using national registries, the authors identified subjects aged 60 to 85 years with prior CTS surgery, where the first procedure on the second wrist was performed 5 to 15 years earlier. Invitations to participate in the study were sent by mail. Per international recommendations, the initial cardiac evaluation included echocardiography, (99)(m)technetium-pyrophosphate scintigraphy, and assessment of monoclonal proteins in serum and urine. RESULTS A total of 250 subjects (35.7% of those invited) participated in the study. The median age was 70.4 years, and 50% were female. CA was diagnosed in 12 patients (4.8%; 95% 0: 2.5%-8.2%), and all cases were wild-type transthyretin amytoidosis (ATTRwt). The prevalence of ATTRwt in men was 8.8% (95% 0: 4.5%-15.2%; n = 11), and 21.2% (95% CI: 11.1%-34.7%) in male subjects >= 70 years with a BMI <30 kg/m(2). All but 2 patients diagnosed with ATTRwt were in the lowest disease severity score (Mayo score). CONCLUSIONS Screening for CA in patients with prior surgery for bilateral CTS finds approximately 5% with earlystage transthyretin CA. The clinical yield was higher (>1 in 5) when focusing on nonobese men >= 70 years, showing potential for systematic screening. (C) 2022 by the American College of Cardiology Foundation.

Specialized palliative care (SPC) is a multidisciplinary need-based approach from the time a life-threatening disease is diagnosed. Patients with multiple myeloma (MM) will, at the time of diagnosis, often present with symptoms and needs that require a multidisciplinary approach. This case describes the course of a patient with newly diagnosed MM, involving all vertebrae and with no common analgesic treatment providing sufficient relief. High symptom burden and psychosocial and existential factors contribute to his total suffering. SPC, anesthesiological, and radio-oncological disciplines are integrated early, and the multidisciplinary approach includes support from social worker, psychologist, and physiotherapist. The needs and distress of the patients' wife are addressed. Barriers for further integration and the role of standardized care pathways are discussed, and the importance of systematic screening for symptoms and needs is highlighted. Integrating several disciplines may be a prerequisite for antineoplastic treatment being initiated for patients with newly diagnosed malignant disease.

In general, governments and health authorities have taken precautions during the COVID-19 pandemic to reduce the viral spread and protect vulnerable citizens. Patients with multiple myeloma (MM) have an increased risk of being infected with COVID-19 and developing a fatal course due to the related immunodeficiency. We investigated how Danish patients with MM reported their quality of life (QoL) pre-COVID and during COVID, in an ongoing longitudinal QoL survey. The responses given during the first and second wave of the COVID-19 pandemic were pooled, analyzed and compared to the same period the year before. We hypothesized that locking down the society would have caused deteriorated QoL and that patients living alone and those under the age of 65 would be particularly affected by the situation. Surprisingly, our study showed the opposite. Statistically significant and clinically relevant differences were primarily found during the first lock down and represented reduced fatigue, improved role functioning, decreased insomnia and improved physical health summaries in patients below 65 years of age. These results indicate that Danish patients with MM might have felt protected and safe by COVID restrictions. Otherwise, the questionaries used in QoL-MM survey may not have been able to capture the impact of the COVID-19 pandemic. Importantly, this indicates that QoL survey data obtained in clinical studies, in countries with highly developed health-care systems using standard questionnaires during the pandemic, allow room for interpretation without being adjusted for the impacts of the pandemic.

Immunotherapy is being thoroughly tested for hematological malignancies. In myelodysplastic syndromes (MDS), greatest focus has been towards vaccines and checkpoint inhibitors (CI). The cancer types, where CI has shown the greatest clinical benefit, are the ones that carry a high mutational burden. Mutations create neoantigens, that can be presented on HLA molecules, and are suggested to be the main mediator of immunogenic cancer cell elimination. MDS carry comparably few mutations in their malignant cells. Therefore, it remains doubtful whether the malignant cells in MDS can be sufficiently immunogenic to generate an adequate immune response when treated with CI. In this study we investigated T cell responses to personal neoantigens in patients with MDS. We ran DNA and RNA sequencing data, from mesenchymal stem cells and CD34+ cells in 15 patients with MDS, through an MHC binding prediction algorithm, to create personal libraries of neo-peptides corresponding to the individual patients’ mutations. Bone marrow samples from the patients were screened for T cell binding to peptide-MHC-multimers (pMHC) coupled with a DNA-barcode, allowing us to look for T cell reactivity against more than 1000 pMHC in parallel. T cell responses were then validated using functional analysis. Current results indicate that several neoepitopes in MDS are indeed immunogenic and are recognized by cytotoxic T cells in the bone marrow. Interestingly, many of the same neoepitopes are also recognized by T cells in healthy donors, but in contrary to the patient samples, neoepitope binding T cells from healthy donors are not functionally active. To our knowledge, this is the first time neoantigens have been detected and functionally verified in the context of MDS. These findings could lead to further explorations into personal neoepitope vaccines, currently tested in other malignancies, and suggests a role for CI in MDS, possibly combined with specific neoepitope targeting. Copy Number Variations Predict Poor Survival in Patients with Idiopathic Cytopenia of Undetermined Significance (ICUS) and are Associated with Macrocytosis SU Mikkelsen,1,2 S Safavi,3 JW Hansen,1,2,4 K Dimopoulos,5 C O’Rourke,2 MK Andersen,3 JB Andersen,2 and K Grønbæk1,2,4 1Department of Hematology, Rigshospitalet; 2BRIC, University of Copenhagen; 3Department of Clinical Genetics, Rigshospitalet; 4DanStem, University of Copenhagen; 5Department of Clinical Biochemistry, Rigshospitalet Approximately half of ICUS patients have somatic mutations associated with increased risk of progression. The cause of cytopenia in the remaining ICUS patients is unknown. We hypothesize that uniparental disomy (UPD) and submicroscopic copy number variations (CNVs; gains and deletions) are present in ICUS patients and may be associated with prognosis. Patients (n=154) referred with ICUS (2008-2017) were included if cytopenia persisted for >6 months, cytogenetics was normal and BM morphology was not diagnostic. SNP-A was performed on DNA from MNCs or granulocytes using Illumina Infinium-CytoSNP-850K and analyzed with GenomeStudio-v1.1 (Illumina). Only dels>30 markers, gains>90 markers and UPD>5Mb were reported. A total of 33 CNVs/UPDs (excluding delY) were detected in 27/154 patients (18%). Mutations were present in 12/27 patients (44%) with CNVs/UPDs. Twenty-six deletions or UPDs (del/UPD) were detected in 21/154 patients (14%) of whom 11/21 (52%) harbored mutations. After a median follow-up of 25 months (range, 2-114), median OS was 67 months (95%CI:19-not reached) in patients with del/UPD and not reached in patients without (p=0.003), Fig.1. The association with poor OS was also significant when including gains (p=0.02), however, the impact seemed driven by del/UPD, and here results with del/UPD are presented. In multivariate analysis, del/UPD (HR=2.7, 95%CI:1.22-5.9, p=0.014) and deep anemia (hgb<6.2) (HR=2.2, 95%CI:1.104.4, p=0.025) were independent adverse prognostic factors for OS, Fig.2. Interestingly, an almost identical pattern was observed between macrocytosis (MCV>100fL) and del/UPD indicating a linked impact on survival. Patients with del/UPD had significantly higher MCV (p=0.005) and Pferritin (p=0.03). Importantly, macrocytosis was not associated with deep anemia (p=0.317). To our knowledge, this is the first study investigating CNVs/UPDs in ICUS patients. Our results suggest that SNP-A can aid the prognostics in ICUS by identifying submicroscopic structural variations as risk markers for poor OS. A possible role of macrocytosis as a surrogate marker should be explored. Figure 2. Forest plot with hazard ratios (HR). Deletions or UPD (Deletions_UPD) and macrocytosis were not included in the same model due to multicollinearity. Cox proportional hazard regression models were used to estimate HRs and associated 95% CIs. Anemia: hgb < 6.2 mM; Mutations: Somatic mutations with a VAF ≥ 5%. Figure 1. Kaplan-Meier survival curves for patients with deletions or UPD (del/UPD) and patients without del/UPD. Median overall survival (OS) was compared using a stratified log-rank test. X axis: Time from first visit (study inclusion) in months. Oral vitamin C supplementation to myeloid cancer patients on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes L.Gillberg,1,2 A.D.Ørskov,1,2 A.Nasif,3 H.Ohtani,4 Z.Madaj,4 J.W.Hansen,1,2,7 N.Rapin,2 J.B. Mogensen,1,2 M.Liu,4 I.H.Dufva,5 J.Lykkesfeldt,6 P.Hajkova,3 P.A.Jones,4 K.Grønbæk1,2,7 1Dept. of Haematology, Rigshospitalet. 2BRIC, University of Copenhagen; 3MRC London Institute of Medical Sciences (LMS), Imperial College, London, UK; 4Van Andel Research Institute, Grand Rapids, Michigan, USA; 5Department of Haematology, Herlev University Hospital; 6Department of Veterinary and Animal Sciences, University of Copenhagen; and 7The Danish Stem Cell Center (Danstem), University of Copenhagen, Denmark. Abstract Purpose: Hematological cancer patients are often vitamin C deficient, and vitamin C is essential for the TET-induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC); the first step in active DNA demethylation. Here, we investigated whether oral vitamin C supplementation can correct vitamin C deficiency, enhance the 5hmC/5mC ratio and upregulate expression of viral defense genes in myeloid cancer patients treated with DNA methyltransferase inhibitors (DNMTis). Experimental design: A randomized, placebo-controlled clinical trial in myeloid cancer patients performed during 3 cycles of DNMTi-treatment (5-azacitidine, 100 mg/m2/d for 5 days in 28-day cycles) supplemented by oral dose of 500 mg vitamin C (n=10) or placebo (n=10) daily during the last 2 cycles (Figure 1). Results: Fourteen patients were deficient in plasma vitamin C (<23 μM) and four of the remaining six patients were taking vitamin supplement at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency (<11.4 μM; P=0.004). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (P=0.0004). We show for the first time that global 5hmC/5mC levels were significantly increased in patients receiving vitamin C compared to placebo (P=0.041). Additionally, preliminary data suggest that vitamin C supplement may increase the upregulation of viral defense genes in DNMTi naïve patients. Conclusions: Normalization of plasma vitamin C by oral supplementation may enhance the biological effects of DNMTis in patients and prompts the investigation of the clinical efficacy of vitamin C supplementation to DNMTis in a large randomized, placebocontrolled trial.Purpose: Hematological cancer patients are often vitamin C deficient, and vitamin C is essential for the TET-induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC); the first step in active DNA demethylation. Here, we investigated whether oral vitamin C supplementation can correct vitamin C deficiency, enhance the 5hmC/5mC ratio and upregulate expression of viral defense genes in myeloid cancer patients treated with DNA methyltransferase inhibitors (DNMTis). Experimental design: A randomized, placebo-controlled clinical trial in myeloid cancer patients performed during 3 cycles of DNMTi-treatment (5-azacitidine, 100 mg/m2/d for 5 days in 28-day cycles) supplemented by oral dose of 500 mg vitamin C (n=10) or placebo (n=10) daily during the last 2 cycles (Figure 1). Results: Fourteen patients were deficient in plasma vitamin C (<23 μM) and four of the remaining six patients were taking vitamin supplement at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency (<11.4 μM; P=0.004). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (P=0.0004). We show for the first time that global 5hmC/5mC levels were significantly increased in patients receiving vitamin C compared to placebo (P=0.041). Additionally, preliminary data suggest that vitamin C supplement may increase the upregulation of viral defense genes in DNMTi naïve patients. Conclusions: Normalization of plasma vitamin C by oral supplementation may enhance the biological effects of DNMTis in patients and prompts the investigation of the clinical efficacy of vitamin C supplementation to DNMTis in a large randomized, placebocontrolled trial. Figure 1. Study design. Days 1, 5, and 28: before 500 mg vitamin C/placebo exposure. Day 32: after short-term vitamin C/placebo exposure. Days 56, 60, and 84: after longerterm vitamin C/placebo exposure. DEPRESSION AND ANXIETY IN HODGKIN LYMPHOMA SURVIVORS: A DANISH NATIONWIDE COHORT STUDY OF 896 PATIENTS Andreas Kiesbye Øvlisen1,2, Lasse Hjort Jakobsen1,2, Kristian Hay Kragholm3, Martin Hutchings4, Christian Bjørn Poulsen5, Henrik Frederiksen6, Danny Stoltenberg7, Martin Bøgsted1,2, Lene Sofie Granfelt Østgård8, Marianne Tang Severinsen1,2,3, Tarec Christoffer El-Galaly1,2,3. 1. De

Purpose The quality of patient-reported outcome (PRO) data can be compromised by non-response (NR) to scheduled questionnaires, particularly if reasons for NR are related to health problems, which may lead to unintended bias. The aim was to investigate whether electronic reminders and real-time monitoring improve PRO completion rate. Methods The population-based study "Quality of life in Danish multiple myeloma patients" is a longitudinal, multicentre study with consecutive inclusion of treatment-demanding newly diagnosed or relapsed patients with multiple myeloma. Education of study nurses in the avoidance of NR, electronic reminders, 7-day response windows and real-time monitoring of NR were integrated in the study. Patients complete PRO assessments at study entry and at 12 follow-up time points using electronic or paper questionnaires. The effect of the electronic reminders and real-time monitoring were investigated by comparison of proportions of completed questionnaires before and after each intervention. Results The first 271 included patients were analysed; of those, 249 (85%) chose electronic questionnaires. Eighty-four percent of the 1441 scheduled PRO assessments were completed within the 7-day response window and 11% after real-time monitoring, achieving a final PRO completion rate of 95%. A significant higher proportion of uncompleted questionnaires were completed after the patients had received the electronic reminder and after real-time monitoring. Conclusions Electronic reminders and real-time monitoring contributed to a very high completion rate in the study. To increase the quality of PRO data, we propose integrating these strategies in PRO studies, however highlighting that an increase in staff resources is required for implementation.

Chemerin is a recently discovered adipokine shown to be involved in both inflammatory and metabolic processes. Here, we demonstrate that chemerin serum levels are elevated in patients with multiple myeloma and that it increases with disease progression. We found that chemerin is expressed by stromal cells and preadipocytes, whereas its receptor CCRL2 is expressed by primary myeloma cells, suggesting a paracrine signaling loop between bone marrow stromal cells/adipocytes and myeloma cells. This is the first study exploring chemerin and its receptors in multiple myeloma.