Introduction Triple-class exposed (TCEx) multiple myeloma (MM) patients previously treated with an immunomodulatory agent (IMiD), proteasome inhibitor, and anti-CD38 monoclonal antibody, represent a heavily pretreated population with limited remaining therapeutic options. Older adults (≥70 years) comprise nearly half of this group, yet data on their real-world treatment patterns and outcomes remain sparse. Objectives To report real-world outcomes in older adults with TCEx MM. Methods We conducted a retrospective study using the Flatiron Health electronic health record–derived de-identified database in adults with MM who became TCEx between November 16, 2015, and December 31, 2024. The index date was defined as the start of the first subsequent line of therapy following TCEx. Patients were stratified by age (<70 vs ≥70 years) at the TCEx date. Outcomes included overall survival (OS) and progression-free survival (PFS), which were estimated using Kaplan–Meier methods. Results Among 6,301 TCEx MM patients, 3,099 (49.2%) were aged ≥70 years. Approximately 51% (n=3,193) received a subsequent treatment, of which 1,426 (44.7%) were aged ≥70 years. The median age was 61 years in the younger cohort and 76 years in the older cohort. Compared to younger patients, the older cohort who received a subsequent treatment had more comorbidities (mean Charlson Comorbidity Index: 2.61 vs 2.40) and lower rates of prior stem cell transplant (30.7% vs 72.3%). The median number of prior lines of therapy (pLOT) was 3.0 for patients aged ≥70 (vs 2.0 in patients aged <70) who received a subsequent treatment post-TCEx. Patients in both cohorts had similar levels of double- and triple-class refractoriness; 11.8% of patients aged <70 were penta-refractory vs 9.5% for patients aged ≥70. Despite similar exposure to 3 key drug classes, older patients were more likely to receive anti-CD38 monotherapy or doublets and less likely to receive a quadruplet as index treatment post-TCEx compared to younger patients. Older patients had shorter median follow-up compared to younger patients (12.7 vs 15.3 months). Median OS among patients aged <70 and aged ≥70 was 46.0 vs 27.3 months and median PFS was 7.0 vs 6.5 months, respectively. Among patients aged ≥70, survival declined with increasing pLOT: median OS was 59.4 months for those initiating index therapy before third line, 26.5 months for those in 3rd or 4th line, and 20.6 months for those in 5th line or beyond. Corresponding median PFS for patients aged ≥70 was 9.7, 6.5, and 5.8 months, respectively. Conclusions Older adults with TCEx MM experienced worse survival outcomes and received fewer triplet-based treatment regimens compared to younger patients. Outcomes deteriorated with increasing pLOT. These findings highlight the urgent need to reevaluate age-adjusted treatment strategies and offer novel therapeutic approaches to improve outcomes in this growing population.

Introduction Chimeric antigen receptor (CAR) T-cell therapies are an effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). Idecabtagene vicleucel (ide-cel) is a B-cell maturation antigen-targeted CAR T-cell therapy approved for patients with RRMM with ≥2 prior lines of therapy. Objectives To present a subgroup analysis from the KarMMa-3 trial (NCT03651128) evaluating efficacy and safety outcomes in older and younger patients with RRMM who received ide-cel or standard therapy. Methods KarMMa-3 is an open-label, phase 3 trial of adults with RRMM who received 2-4 prior treatment regimens with disease refractory to the last therapy. Enrolled patients were randomized (2:1) to receive either a one-time infusion of ide-cel or 1 of 5 standard regimens. The efficacy and safety of ide-cel compared with standard regimens were evaluated by age (≥70 vs <70 y). Outcome measures assessed include overall response rate (ORR), progression-free survival (PFS), overall survival (OS), patient-reported quality of life (QoL), and incidence of selected adverse events. Results A total of 386 patients were evaluated; 19.3% (49/254) of those receiving ide-cel and 20.5% (27/132) of those receiving standard regimens were aged ≥70 y. Compared with older patients, younger patients receiving ide-cel exhibited more high-risk baseline characteristics, including high-risk cytogenic abnormalities (44.4% vs 32.7%) and triple-class refractory disease (66.8% vs 55.1%).ORR for patients aged <70 y was 68.8% (95% CI, 62.4%-75.1%) with ide-cel and 41.0% (31.5%-50.4%) with standard regimens (P<0.0001). Patients aged ≥70 y treated with ide-cel achieved an ORR of 81.6% (95% CI, 70.8%-92.5%) vs 48.1% (29.3%-67.0%) with standard regimens (P<0.01). Median PFS for patients aged <70 y was longer with ide-cel treatment vs standard regimens (12.5 mo [95% CI, 11.2-15.4] vs 4.2 mo [3.5-5.7]; P<0.0001). In patients aged ≥70 y, median PFS was 18.9 mo (95% CI, 12.1-24.5) with ide-cel treatment and 5.7 mo (2.2-12.2) with standard regimens (P<0.01). Median OS was not reached (NR) in older patients in either treatment arm; in younger patients, median OS was 39.5 mo (95% CI, 27.8-NR) with ide-cel and 27.9 mo (20.6-NR) with standard regimens. Incidence of adverse events reported with ide-cel treatment was similar between age groups for cytokine release syndrome, neurotoxicity, and infections. Analyses of patient-reported QoL data and other relevant safety endpoints are ongoing. Conclusions In KarMMa-3, older patients derived substantial benefit from ide-cel treatment, demonstrated by longer PFS and a notable ORR compared with standard regimens. Efficacy and safety outcomes were consistent across age groups, reinforcing the potential for durable benefit with a single ide-cel infusion in a real-world context without additional adverse safety signals.

Here we aim to evaluate the relationship between progression-free survival (PFS) and patient-reported symptoms (measured by health-related quality of life scores) among patients with relapsed/refractory multiple myeloma (RRMM). Pain and fatigue were identified as the most common patient-relevant symptoms within RRMM based on a predefined literature review of patient preference/qualitative studies (confirmed by clinical experts). Consequently, the European Organisation for Research and Treatment of Cancer QLQ-C30 pain, QLQ-MY20 disease symptoms (pain in different locations), and QLQ-C30 fatigue domains were selected. Change from baseline scores per symptom domain was jointly modeled with PFS assuming a current slope association structure. For each symptom, we evaluated trial-specific joint models based on individual patient data from 7 RRMM clinical trials. The association between symptoms and PFS was summarized via association-effect hazard ratios (HRs) from the joint models, where a HR > 1 indicates that symptom worsening was associated with an increased hazard of a progression/death event. Meta-analyses were performed to synthesize the joint model HRs from all trials into one summary statistic (meta-HR) per symptom domain. Across trials, worsening in pain and fatigue was associated with an increased hazard of progression events (disease progression/death) based on joint-model-association-effect HRs. Specifically, meta-HRs (95

Idecabtagene vicleucel (ide-cel) is an anti-BCMA CAR-T cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM) after 2 prior lines of therapy. There is limited data on outcomes of CAR T in older adults and frail patients with RRMM. In this study, we utilized data from the Center for International Blood and Marrow Transplantation Registry to describe the safety and efficacy of ide-cel in these clinically important subgroups. An adapted version of the previously described simplified frailty index (SFI) was used to assess frailty. A total of 821 pts were followed for a median of 11.6 months (m, range, 1.1 - 26.7 m). Of these patients, 251 (30.6%) were ≥70 years of age. Older adults had higher rates of immune-effector cell associated neurotoxicity syndrome (ICANS) of any grade (37.1% vs 24.2%, p<0.01), but there were no differences in grade ≥3 ICANS or cytokine release syndrome (CRS, any grade or grade≥3). Older adults had improved progression-free survival (PFS) which remained significant in a multivariable model. There was no significant difference in treatment related mortality (TRM). Frail patients (343/766) had a higher rate of ICANS of any grade (37% versus 21.5%, p<0.01) and clinically significant infections (49.6% vs 40.9%, p=0.02), but there were no significant differences in grade ≥3 ICANS, CRS, response, PFS, overall survival or TRM.In conclusion, older adults and frail patients with RRMM had comparable efficacy to younger and non-frail patients, respectively. These patients were at higher risk of developing ICANS but had no increase in other adverse events.

ABSTRACT:Idecabtagene vicleucel (ide-cel) was the first US Food and Drug Administration-approved chimeric antigen receptor T-cell (CAR-T) therapy for multiple myeloma (MM). However, because clinical trials are highly selective with stringent eligibility criteria, the objective of this study was to evaluate the safety and effectiveness of standard-of-care (SOC) ide-cel in the real world. Using the Center for International Blood and Marrow Transplant Research registry, we evaluated 821 patients who received SOC ide-cel. Median follow-up was 11.6 months. Median age was 66 years, and the cohort included 31% patients aged ≥70 years, with 15% Black and 7% Hispanic, and 77% of patients with ≥1 significant comorbidity. The median number of prior lines of therapy was 7, 15% patients previously received B-cell maturation antigen-directed therapy, 17% had extramedullary disease, and 27% had high-risk cytogenetics. Overall response rate was 73%, and complete response rate was 25%. Median progression-free survival was 8.8 months. Treatment-related mortality was reported in 6% of patients. Cytokine release syndrome was diagnosed in 80% of patients (grade ≥3, 3%). Immune effector cell-associated neurotoxicity syndrome was observed in 28% (grade ≥3, 5%), with no cases of Parkinsonism reported. Clinically significant infections were seen in 45% of patients. Second primary malignancies were reported in 4%, including 1% myeloid malignancies. This is, to our knowledge, the largest real-world study of ide-cel CAR-T therapy in patients with relapsed/refractory (R/R) MM. We observed a favorable safety and efficacy profile that mirrors trial experience, even in the setting of significant comorbidities in 77% of patients, many of which would have made them ineligible for the registrational KarMMa clinical trial. This trial was registered at www.clinicaltrials.gov as #NCT03361748.

Introduction: Patients with triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM) have historically experienced poor clinical outcomes, prompting the development of novel therapeutic options. Idecabtagene vicleucel (ide-cel) was the first chimeric antigen receptor (CAR) T cell therapy approved for this population, while teclistamab became the first approved bispecific antibody. Both target B-cell maturation antigen (BCMA) and are increasingly used in real-world (RW) settings. Most comparative evidence to date is derived from single-arm clinical trials with cross-trial adjustments. RW studies offer an opportunity to directly compare these therapies and assess their relative effectiveness in routine clinical practice. Methods: We conducted a comparative effectiveness analysis of ide-cel and teclistamab in patients with TCE RRMM using RW data from the United States Flatiron Health electronic health record-derived, deidentified database (January 2011 to April 2025 data cut). Adults who received either index therapy at any line of treatment after becoming TCE (ie, previously exposed to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody) were included. Exclusion criteria were prior exposure to CAR T cell therapy, bispecific antibodies, or belantamab mafodotin; absence of index treatment; or lack of post-index follow-up. Index dates (T0) represent the date of infusion for ide-cel and the start of treatment for teclistamab. Seventeen prognostic covariates were selected a priori based on published rankings and used to balance treatment groups via inverse probability of treatment weighting (IPTW) with average treatment effect weights. Cox proportional hazards models were used to estimate unadjusted and IPTW-adjusted HRs with 95% CIs for progression-free survival (PFS) and overall survival (OS). As the ide-cel cohort only included infused patients, additional analyses were performed to emulate a real-world intention-to-treat population given the potential immortal time bias (patients in the ide-cel cohort were required to survive between apheresis and infusion). Specifically, patients in the teclistamab cohort who died within the first 24 days (median turnaround time for ide-cel manufacturing in United States in 2024) were excluded and 2 scenarios were performed to re-align T0 based on this 24-day period (either shifting teclistamab T0 forward or ide-cel T0 backward). Lastly, sensitivity analyses assessed differences in restricted mean survival time (dRMST) at 12 and 24 months. Results: A total of 281 patients met the inclusion criteria (ide-cel, N=106; teclistamab, N=175), with median follow-up of 22.4 and 13.7 months, respectively. IPTW adjustment balanced all covariates between groups (effective sample size: ide-cel, n=68; teclistamab, n=135). Adjusted analyses showed improved PFS with ide-cel versus teclistamab (HR, 0.67; 95% CI, 0.47–0.97), with median PFS of 11.3 versus 6.5 months. OS was also improved with ide-cel (HR, 0.59; 95% CI, 0.35–0.98); median OS was not reached in either group due to insufficient follow-up. There was a consistent trend of HRs favoring ide-cel versus teclistamab for both PFS and OS in both scenario analyses addressing the potential immortal time bias. Further, sensitivity analyses using dRMST confirmed statistically significant improvements in both PFS and OS with ide-cel across all scenarios at all time points evaluated. Conclusions: In this RW analysis, ide-cel was associated with superior PFS and OS compared with teclistamab in patients with TCE RRMM. These findings support emerging RW evidence favoring BCMA-directed CAR T cell therapies over bispecific antibodies and may inform treatment sequencing decisions in this high-risk population.

BackgroundIdecabtagene vicleucel (ide-cel) is an anti-BCMA CAR-T cell therapy approved for patients with triple-class exposed relapse/refractory multiple myeloma after 4 prior lines of therapy. There is limited data on outcomes in older adults and frail patients. In this study, we describe the safety and efficacy of ide-cel in these clinically important subgroups treated in a real-world setting.MethodsWe included all US patients in the CIBMTR registry receiving ide-cel infusion from May 2021 to June 2023, with a conforming product with at least 3 months (m) of follow-up. An age cut-off of ≥70 years (y) was used to define older patients (pts). To assess frailty, we used an adapted version of the previously described simplified frailty index (SFI, Facon et al, Leukemia 2020). This combines an assessment of age (76-80 years, 1 point, >80 years, 2 points), performance status (ECOG PS 1, 1 point, ECOG PS ≥2, 2 points) and comorbidity for which we used the hematopoietic cell transplantation specific comorbidity index (HCT-CI) in lieu of the Charlson comorbidity index (score of ≥2, 1 point, as in original publication). Patients were classified as frail (score ≥2) or non-frail (score 0-1). Primary endpoints included response and progression-free survival (PFS). Secondary endpoints included overall survival (OS), treatment-related mortality (TRM), prolonged cytopenia (>3 months), clinically significant infections (CSI), cytokine-release syndrome (CRS), and neurotoxicity (NT).ResultsA total of 686 pts were followed for a median of 6.9 m (range, 1.1 – 20.5 m); 198 (28.9%) were older adults (OA, age ≥70 y). Baseline characteristics were largely comparable between OA and pts <70 y (Table 1). There were no significant differences in rates of overall response (77.8% vs 69.7%, p=0.07) and complete response (26.3% vs 25%, p=0.90). OA had a superior 6-m PFS (69.6% vs 59.5%, p<.01). No significant differences in 6-m OS (85.8% vs 82.6%, p=0.14) or TRM (4.7% vs 2.5%, p=0.21) were noted. OA had higher rates of neurotoxicity (NT) of any grade (38.9% vs 25.8%, p<.01), but there were no differences in grade ≥3 NT, CRS (any grade or grade≥3), rates-of or time-to-recovery from NT or CRS, prolonged cytopenia or CSI.Using the adapted SFI, frailty scores could be calculated for 642/686 patients of whom 292 (45.5%) were classified as frail. Baseline characteristics were largely balanced, except for lower rates of extramedullary disease in the frail group (8.2% vs 12.3%, p=.03). Frail pts had higher rates of prolonged cytopenia (33.6% vs 26.6%, p=.04), CSI (49.7% vs 38.6%, p<.01) and NT (any grade, 38% vs 23.7%, p<.01) but there were no significant differences in grade ≥3 NT, CRS (any grade or grade ≥3), response, PFS, OS or TRM (see Table 1).ConclusionOlder adults and frail patients treated with ide-cel have comparable efficacy outcomes to younger and non-frail patients respectively, without increase in high-grade adverse events.

Patient-reported outcome (PRO) questionnaires considered in this paper contain multiple subscales, although not all subscales are equally relevant for administration in all target patient populations. A group of measurement experts, developers, license holders, and other scientific-, regulatory-, payer-, and patient-focused stakeholders participated in a panel to discuss the benefits and challenges of a modular approach, defined here as administering a subset of subscales out of a multi-scaled PRO measure. This paper supports the position that it is acceptable, and sometimes preferable, to take a modular approach when administering PRO questionnaires, provided that certain conditions have been met and a rigorous selection process performed. Based on the experiences and perspectives of all stakeholders, using a modular approach can reduce patient burden and increase the relevancy of the items administered, and thereby improve measurement precision and eliminate wasted data without sacrificing the scientific validity and utility of the instrument. The panelists agreed that implementing a modular approach is not expected to have a meaningful impact on item responses, subscale scores, variability, reliability, validity, and effect size estimates; however, collecting additional evidence for the impact of context may be desirable. It is also important to recognize that adequate rationale and evidence (e.g., of fit-for-purpose status and relevance to patients) and a robust consensus process that includes patient perspectives are required to inform selection of subscales, as in any other measurement circumstance, is expected. We believe that the considerations discussed within (content validity, administration context, and psychometric factors) are relevant across multiple therapeutic areas.

Objectives: Multilevel network meta-regression (ML-NMR) leverages individual patient data (IPD) and aggregate data from a network of randomized controlled trials (RCTs) to assess the comparative efficacy of multiple treatments, while adjusting for between-study differences. We provide an overview of ML-NMR for time-to-event outcomes and apply it to an illustrative case study, including example R code. Methods: The case study evaluated the comparative efficacy of idecabtagene vicleucel (ide-cel), selinexor1dexamethasone 1 dexamethasone (Sd), belantamab mafodotin (BM), and conventional care (CC) for patients with triple-class exposed relapsed/refractory multiple myeloma in terms of overall survival. Single-arm clinical trials and real-world data were naively combined to create an aggregate data artificial RCT (aRCT) (MAMMOTH-CC versus DREAMM-2-BM versus STORM-2-Sd) and an IPD aRCT (KarMMa-ide-cel versus KarMMa-RW-CC). With some assumptions, we incorporated continuous covariates with skewed distributions, reported as median and range. The ML-NMR models adjusted for number of prior lines, triple-class refractory status, and age and were compared using the leave-one-out information criterion. We summarized predicted hazard ratios and survival (95% credible intervals) in the IPD aRCT population. Results: The Weibull ML-NMR model had the lowest leave-one-out information criterion. Ide-cel was more efficacious than Sd, BM, and CC in terms of overall survival. Effect modifiers had minimal impact on the model, and only triple-class refractory was a prognostic factor. Conclusions: We demonstrate an application of ML-NMR for time-to-event outcomes and introduce code that can be used to aid implementation. Given its benefits, we encourage practitioners to utilize ML-NMR when population adjustment is necessary for comparisons of multiple treatments.

Introduction A single ide-cel infusion showed significantly longer median progression-free survival (PFS) vs std regimens (13.3 vs 4.4 months [mo], HR 0.49, 95% CI 0.38-0.65, P < 0.001) with deep, durable responses in heavily pretreated TCE RRMM at an interim analysis (IA) of KarMMa-3 (NCT03651128); safety data were consistent with prior studies (Rodríguez-Otero et al. NEJM 2023). Ide-cel benefits were consistent across pts in high-risk subgroups and across 2-4 prior lines of therapy (Tx). Results of the preplanned final PFS analysis of KarMMa-3 with 12.3 mo additional follow-up are reported. Methods In the phase 3 KarMMa-3 trial, pts with RRMM who received 2-4 prior regimens, including an immunomodulatory agent, proteasome inhibitor, and daratumumab, and were refractory to last regimen were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd). In the ide-cel arm, pts could receive ≤ 1 cycle of optional bridging Tx for disease control. Pts in the std regimens arm could receive ide-cel after confirmed disease progression (PD). The primary endpoint was IRC-assessed PFS in the ITT population; final PFS was planned to be analyzed with ~289 events. Key secondary endpoints were IRC-assessed overall response rate (ORR) and overall survival (OS); other secondary endpoints included complete response rate (CRR), duration of response (DOR), minimal residual disease (MRD) status, time to next anti-myeloma Tx (TTNT; time from randomization to next anti-myeloma Tx [MTx]), event-free survival (EFS; time from randomization to first PD, next MTx or any-cause death, whichever is first), PFS2 (time from randomization to second objective PD or any-cause death, whichever is first), safety, and health-related quality of life (QOL). Results Of 386 randomized pts (ide-cel, n = 254; std regimens, n = 132), 225 received ide-cel and 126 received a std regimen. Baseline characteristics were generally balanced. Median follow-up from randomization to data cutoff (April 28, 2023) was 30.9 mo (range 12.7-47.8). Ide-cel significantly improved median PFS (95% CI) vs std regimens (13.8 [11.8-16.1] vs 4.4 [3.4-5.8] mo), representing a 51% reduced risk of PD or death (HR 0.49, 95% CI 0.38-0.63; Figure); 18 mo PFS rates were 41% vs 19%, respectively. Ide-cel significantly improved ORR vs std regimens (71% vs 42%) with deeper (CRR 44% vs 5%; ≥CR and MRD negative status [sensitivity level 10 -5], 22% vs 1%), more durable responses (median DOR 16.6 vs 9.7 mo; Table). PFS and ORR benefits of ide-cel vs std regimens were consistent with the IA. Interim OS will be included in the presentation. In pts who received ide-cel (n = 225) or a std regimen (n = 126), median PFS (95% CI) was 15.7 (12.5-18.9) vs 4.4 (3.4-5.8) mo, respectively. In the ITT population, median TTNT, EFS, and PFS2 were numerically longer with ide-cel vs std regimens. Median (range) TTNT was 20.9 (16.6-24.2) vs 7.0 (5.3-8.5) mo. Median (95% CI) EFS was 13.3 (11.3-15.7) vs 3.9 (3.0-5.3) mo. Median PFS2 (95% CI) was 23.5 (18.4-27.9) vs 16.7 (12.2-20.3) mo; ide-cel was next MTx in 70 (53%) pts in the std regimens arm. In the treated population, grade (gr) 3/4 infections occurred in 66/249 (27%) pts in the ide-cel arm vs 25/126 (20%) in the std regimens arm. In the ide-cel safety population, any gr cytokine release syndrome occurred in 197/225 (88%) pts, gr ≥ 3 in 11 (5%); median time to first onset was 1 d (1-14), median duration was 4 d (1-51). Any gr investigator-identified neurotoxicity occurred in 34/225 (15%) pts, gr ≥ 3 in 7 (3%); median time to onset was 3 d (range 1-317); median duration was 2.5 d (range 1-252). Ide-cel continued to demonstrate durable, clinically meaningful improvements in pt-reported outcomes, including symptoms, functioning, and QOL vs std regimens. Conclusions In this final PFS analysis of KarMMa-3, significantly longer PFS was maintained with ide-cel; PD or death risk reduced by 51%; responses were deeper and more durable vs std regimens. CRR with ide-cel increased since the IA, indicating a deepening response, but were unchanged with std regimens. A single ide-cel infusion vs continuous treatment with std regimens resulted in longer median TTNT and PFS2, indicating improved long-term disease control. The ide-cel safety profile was consistent with previous reports, with no parkinsonism or Guillain-Barré syndrome reported. These data continue to support use of ide-cel in pts with TCE RRMM. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Outcomes are poor in triple-class-exposed (TCE) relapsed/refractory multiple myeloma (RRMM). In the phase 3 KarMMa-3 (clinicaltrials.gov; NCT03651128) trial, patients with TCE RRMM and 2-4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary endpoint; 13.3 vs 4.4 months; P<.0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio (HR), 0.49; 95% confidence interval (CI), 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median (95% CI) was 41.4 (30.9-not reached [NR]) vs 37.9 (23.4-NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE RRMM. NCT03651128

•Estimating thresholds for clinically meaningful change is important when using patient-reported outcomes in clinical research, and the method used to derive these thresholds has implications for their conceptual value and subsequent use in analyses. Additionally, methodology for estimating meaningful change thresholds has progressed in recent years. This review provides a recent, unique snapshot of the role and evolution of meaningful change thresholds for 2 popular quality-of-life instruments (EORTC QLQ-C30 and the FACT-G) across a variety of cancers (hematological, melanoma, lung, bladder, and prostate), synthesizing clinical research, academic, and regulatory perspectives. Specifically, this paper provides a simplified framework to researchers for understanding the recent history of applied score interpretation in oncology for these instruments (ie, legacy, contemporary, and cancer-specific thresholds); it also reviews the application and derivation of thresholds, and finally, synthesizes these findings with regulatory usage through a review of the application of thresholds in clinical trials used in recent drug approvals.•This review contributes to the current literature by highlighting current practices as well as identifying patterns and trends for meaningful change thresholds for the EORTC QLQ-C30 and FACT-G as applied to oncology clinical trials and label claims. This review provides more consistency in application of threshold score interpretation across trials through providing readers with an understanding of the many variables that threaten such consistency (including use of group- or individual-level thresholds, different estimation methods, and differing application of these across trials and cancers).•Findings from this review foster an awareness of the link between current issues in score estimation methodology and subsequent estimated thresholds, which is relevant both to oncology researchers and those working toward regulatory approval of novel therapeutic products. Understanding these issues will help this field to move away from over-reliance on broad “legacy” thresholds and encourage researchers to utilize improved threshold estimates in consideration of specific patient populations, direction of change, and specific domains of the QLQ-C30 and FACT-G instruments.