Patient perspectives on BCMA-targeted therapies for multiple myeloma: a survey conducted in a patient advocacy group.

Background: Advances in multiple myeloma (MM) treatment have shifted the therapeutic landscape. Understanding patients' perspectives can assist physicians in helping patients make informed decisions. This study aimed to understand the patient decision-making process and gain insights into patient perspectives on B-cell maturation antigen (BCMA)-targeted therapies for MM. Methods: An 18-question survey was completed by patients with MM enrolled in HealthTree® Cure Hub, an online portal helping patients with plasma cell dyscrasias navigate their disease. Results: From October 28, 2022, to January 12, 2023, 325 patients with MM participated in the survey. The mean age (standard deviation) of the respondents was 66 (8) years; 54% were female and 90% were White. Among 218 patients with complete clinical records in the database, the median (min, max) lines of therapy (LOT) was 2 (1,16). Among 61 (28%) patients who had received ≥4 LOTs, 55 (90%) were triple-class exposed. Of the 290 patients who responded to the question about openness to new therapies, 76 (26%) were open to trying a new therapy immediately and 125 (43%) wanted more information on safety and efficacy. Most respondents reported likely or very likely to try a BCMA CAR T-cell therapy (60%) or a bispecific antibody (74%) and some needed more information to decide (16% for CAR T-cell therapy and 13% for bispecific antibody). The most requested information included efficacy, side effects (SEs), eligibility, and administration process for both CAR T-cell and bispecific therapies. When 2 therapies with the same efficacy and duration of response were offered, 69% of respondents would prefer the therapy with a lower risk of severe SEs but requires continuous dosing with no treatment-free interval, and 31% preferred a therapy given once followed by a treatment-free interval but with a potentially higher risk of severe SEs. To receive an effective therapy, the top acceptable trade-offs included frequent monitoring of SEs and initiating a new therapy in a hospital setting, and the least acceptable compromise was caregiver burden. Conclusions: This study found a high level of openness in patients with MM to try BCMA-targeted therapies. Information on efficacy, safety, availability, and eligibility may assist patients on decision-making.

Multiple myeloma: a paradigm for blending community and academic care.

The care of the multiple myeloma (MM) patient is complex, with most patients requiring multiple lines of therapy over a span of many years to decades. Since the days when autologous stem cell transplantation became the standard of care for a large subset of patients, it was imperative that community practices and specialized academic centers work together to optimize the initial care of patients. Now, with the unprecedented number of treatment options and the introduction of chimeric antigen receptor T-cell therapies and bispecific T-cell engagers, that collaboration has become even more important and stretches from the upfront treatment to the relapsed and refractory disease setting. I will discuss the unique safety profile and logistical aspects that pose challenges and opportunities for the safe and successful delivery of these therapies. Close interaction, communication, and established partnerships between the primary oncologist, the myeloma specialist, and the transplant or immune effector cell provider will be required to provide the optimal care longitudinally for each patient. This multidisciplinary approach to treating MM can serve as a paradigm for blending community and academic care.

Ciltacabtagene Autoleucel in Patients With Prior Allogeneic Stem Cell Transplant in the CARTITUDE-1 Study.

BACKGROUND: Patients with prior allogeneic stem cell transplant (alloSCT) are typically excluded from trials of chimeric antigen receptor (CAR) T cell therapies, because their engineered cells may include allogeneic T cells. Ciltacabtagene autoleucel (cilta-cel) demonstrated early, deep, durable responses and manageable safety in heavily pretreated relapsed/refractory multiple myeloma patients. We retrospectively analyzed patients who received alloSCT prior to cilta-cel in CARTITUDE-1. PATIENTS AND METHODS: Patients eligible for CARTITUDE-1 were ≥18 years, had ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and had received a PI, IMiD, and anti-CD38 antibody. Patients with active graft-versus-host disease (GVHD) or had alloSCT within 6 months before apheresis were excluded. Patients received cilta-cel 5 to 7 days after lymphodepletion. RESULTS: Patients (N = 7) received median 9 prior LOTs (range, 6-14); median time since alloSCT was 5.1 years (range, 2.7-6.2). At median follow-up 27.7 months after cilta-cel infusion, overall response rate was 85.7% (n = 6). The safety profile was generally consistent with patients without alloSCT as prior therapy (cytokine release syndrome, 85.7% vs. 95.6%, respectively; immune effector cell-associated neurotoxicity syndrome, 14.3% vs. 16.7%). One patient with prior alloSCT had grade 3 movement and neurocognitive treatment-emergent adverse events/parkinsonism. No GVHD cases were reported. Two patients died due to adverse events (treatment-related lung abscess; unrelated liver failure). CONCLUSION: Cilta-cel efficacy and safety were comparable between CARTITUDE-1 patients with and without prior alloSCT. Additional studies are needed to fully elucidate the suitability of CAR-T cell therapy in the post-alloSCT setting.

Idecabtagene vicleucel for relapsed and refractory multiple myeloma: post hoc 18-month follow-up of a phase 1 trial.

Idecabtagene vicleucel (ide-cel) is a B-cell-maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy. We performed a post hoc analysis of a single-arm phase 1 multicenter study in relapsed/refractory multiple myeloma (CRB-401) (n = 62; median follow-up, 18.1 months). The primary endpoint was safety outcomes, and secondary endpoints included overall response rate (ORR), complete response (CR) and very good partial response (VGPR). The study met its primary endpoint with low rates of grade 3/grade 4 cytokine release syndrome (6.5%) and neurotoxicity (1.6%). ORR was 75.8%; 64.5% achieved VGPR or better and 38.7% achieved CR or stringent CR. Among exploratory endpoints, median duration of response, progression-free survival (PFS) and overall survival were 10.3, 8.8 and 34.2 months, respectively, and ide-cel expansion in blood and bone marrow correlated with clinical efficacy and postinfusion reduction of soluble BCMA. Patients with PFS ≥ 18 months had more naive and less exhausted T cells in apheresis material and improved functional T cell phenotype in the drug product compared with those with less durable responses. These results confirm ide-cel safety, tolerability and efficacy and describe T cell qualities that correlate with durable response. Clinicaltrials.gov identifier : NCT02658929 .

Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma.

BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide. METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1. RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9). CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).

Plain language summary of the CARTITUDE-1 study of ciltacabtagene autoleucel for the treatment of people with relapsed or refractory multiple myeloma.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a clinical study called CARTITUDE-1. This study tested the anti-cancer chimeric antigen receptor-T cell (CAR-T) therapy ciltacabtagene autoleucel, abbreviated as cilta-cel, in people with multiple myeloma, a cancer that affects a specific type of blood cell called plasma cells. The participants in this study had relapsed or refractory disease, which means that their cancer did not improve or returned after 3 or more previous anti-cancer treatments. HOW WAS THE STUDY IN THIS SUMMARY CONDUCTED?: Ninety-seven participants went through the treatment process, which included collecting participants' own T cells (a type of immune cell), genetically modifying those T cells to recognize a certain protein found on myeloma cancer cells, pretreating with chemotherapy to prepare the participant's immune system to accept the modified T cells (cilta-cel), and finally injecting cilta-cel. WHAT WERE THE RESULTS OF THIS STUDY?: Ninety-eight percent of participants showed decreases in indicators of cancer after treatment with cilta-cel. Seventy percent of participants were still alive approximately 28 months after treatment, and 55% of participants were still living without their cancer getting worse. The most common side effects were low blood cell levels, infections, cytokine release syndrome (a potentially serious side effect caused by overactivation of the immune system), and side effects that involved the nervous system (called neurotoxicities). Some participants experienced late-onset symptoms of neurotoxicity like the signs and symptoms of parkinsonism, meaning that they affected people's movement. Improvements in recognition of factors that increase the risk of these late-onset neurotoxicities and strategies to help avoid them has reduced their occurrence, although long-term monitoring for side effects is still an important part of treatment. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, almost all participants treated with cilta-cel had long-term reductions in signs of myeloma, and the majority of participants were alive and had no detectable signs of cancer over 2 years after being injected with cilta-cel. Clinical Trial Registration: NCT03548207 (1b/2 CARTITUDE-1 study) NCT05201781 (Long-term Follow-up Study for Participants Previously Treated With Ciltacabtagene Autoleucel).

Time-Dependent Prognostic Value of Serological and Measurable Residual Disease Assessments after Idecabtagene Vicleucel.

The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus

Recommendations on prevention of infections during chimeric antigen receptor T-cell and bispecific antibody therapy in multiple myeloma.

Chimeric antigen receptor T (CAR T) cell and bispecific antibody therapies have shown unprecedented efficacy in heavily pretreated patients with multiple myeloma (MM). However, their use is associated with a significant risk of severe infections, which can be attributed to various factors such as hypogammaglobulinemia, neutropenia, lymphopenia, T-cell exhaustion, cytokine-release syndrome and immune-effector cell-associated neurotoxicity syndrome. As these therapies have been recently approved by regulatory agencies, it is crucial to establish practical guidelines for infection monitoring and prevention until robust data from prospective clinical trials become available. To address this issue, a panel of experienced investigators from the Academic Consortium to Overcome Multiple Myeloma through Innovative Trials (COMMIT) developed consensus recommendations for mitigating infections associated with CAR T-cell and bispecific antibody therapies in MM patients.

SOHO State-of-the-Art Updates and Next Questions | BCMA-Directed CAR T-Cells: Early Results and Future Directions.

Despite continued advances that have led to improved survival of patients with multiple myeloma (MM) over the years, MM remains largely incurable with overall survival in patients who have progressed after proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody therapy measured in months. Better understanding of the immunopathology of MM has led to the discovery of newer treatment targets like B-cell maturation antigen (BCMA). BCMA is a tumor necrosis factor receptor superfamily expressed on normal B-lymphocytes and malignant plasma cells with a vital role in proliferation, maturation, and differentiation of normal and malignant plasma cells. Antibody drug conjugates, chimeric antigen receptor (CAR) T-cells and bispecific T-cell engagers targeting the BCMA antigen are now available within and outside of clinical trials for treatment of triple class refractory MM. This review article focuses on the evolution, safety, efficacy, and limitations of BCMA-directed CAR T-cell therapies. It also discusses the challenges unveiled by the incorporation of these CAR T-cells in the treatment paradigm of MM and deliberates on the future of CAR T-cell therapy within MM.

Rates of Influenza and Pneumococcal Vaccination and Correlation With Survival in Multiple Myeloma Patients.

BACKGROUND: Infections are a common reason for hospitalization and death in multiple myeloma (MM). Although pneumococcal vaccination (PV) and influenza vaccination (FV) are recommended for MM patients, data on vaccination status and outcomes are limited in MM. MATERIALS AND METHODS: We utilized data from the global, prospective, observational INSIGHT MM study to analyze FV and PV rates and associated outcomes of patients with MM enrolled 2016-2019. RESULTS: Of the 4307 patients enrolled, 2543 and 2500 had study-entry data on FV and PV status. Overall vaccination rates were low (FV 39.6%, PV 30.2%) and varied by region. On separate multivariable analyses of overall survival (OS) by Cox model, FV in the prior 2 years and PV in the prior 5 years impacted OS (vs. no vaccination; FV: HR, 0.73; 95% CI, 0.60-0.90; P = .003; PV: HR, 0.51; 95% CI, 0.42-0.63; P < .0001) when adjusted for age, region, performance status, disease stage, cytogenetics at diagnosis, MM symptoms, disease status, time since diagnosis, and prior transplant. Proportions of deaths due to infections were lower among vaccinated versus non-vaccinated patients (FV: 9.8% vs. 15.3%, P = .142; PV: 9.9% vs. 18.0%, P = .032). Patients with FV had generally lower health resource utilization (HRU) versus patients without FV; patients with PV had higher or similar HRU versus patients without PV. CONCLUSION: Vaccination is important in MM and should be encouraged. Vaccination status should be recorded in prospective clinical trials as it may affect survival. This trial was registered at www. CLINICALTRIALS: gov as #NCT02761187.

Adjusted comparison of outcomes between patients from CARTITUDE-1 versus multiple myeloma patients with prior exposure to proteasome inhibitors, immunomodulatory drugs and anti-CD38 antibody from the prospective, multinational LocoMMotion study of real-world clinical practice.

Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy studied in patients with multiple myeloma exposed to three classes of treatment in the single-arm CARTITUDE-1 study. To assess the effectiveness of cilta-cel compared to real-world clinical practice (RWCP), we performed adjusted comparisons using individual patients' data from CARTITUDE-1 and LocoMMotion, a prospective, multinational study of patients with multiple myeloma triple-class exposed of treatment. Comparisons were performed using inverse probability weighting. In CARTITUDE-1, 113 patients were enrolled, and 97 patients were infused with cilta-cel. In LocoMMotion, 248 patients were enrolled, and 170 patients were included in the comparisons versus infused patients. Ninety-two unique regimens were used in LocoMMotion, most frequently carfilzomib-dexamethasone (13.7%), pomalidomide-cyclophosphamide-dexamethasone (13.3%) and pomalidomidedexamethasone (11.3%). Adjusted comparisons showed that patients treated with cilta-cel were 3.12-fold more likely to respond to treatment than those managed by RWCP (response rate, 3.12, 95% confidence interval [95% CI]: 2.24-4.00), had their risk of progression or death reduced to by 85% (progression-free survival hazard ratio=0.15, 95% CI: 0.08-0.29), and a risk of death lowered by 80% (overall survival hazard ratio HR=0.20, 95% CI: 0.09-0.41). The incremental improvement in healthrelated quality of life from baseline for cilta-cel versus RWCP at week 52, as measured by EORTC QLQ-C30 Global Health Status, was 13.4 (95% CI: 3.5-23.6) and increased to 30.8 (95% CI: 21.8-39.8) when including death as additional information regarding patients' health status. Patients treated with cilta-cel experienced more adverse events than those managed with RWCP (any grade: 100% vs. 83.5%). The results from this study demonstrate improved efficacy outcomes of cilta-cel versus RWCP and highlight its potential as a novel and effective treatment option for patients with multiple myeloma triple-class exposed of antimyeloma treatment. CARTITUDE-1 is registered with clinicaltrials gov. Identifier: NCT03548207. LocoMMotion is registered with clinicaltrials gov. Identifier: NCT04035226.

Patient Perceptions Regarding Ciltacabtagene Autoleucel Treatment: Qualitative Evidence From Interviews With Patients With Relapsed/Refractory Multiple Myeloma in the CARTITUDE-1 Study.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), a novel chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated early, deep, and durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), and improvements in health-related quality of life (HRQoL) in CARTITUDE-1 (NCT03548207). Patient perspectives on treatment provide context to efficacy outcomes and are an important aspect of therapeutic evaluation. METHODS: Qualitative interviews were conducted in a subset of CARTITUDE-1 patients (n = 36) at screening, Day 100, and Day 184 post cilta-cel on living with MM, therapy expectations, and treatment experiences during the study. RESULTS: Patients most wanted to see change in symptoms with the greatest impact on HRQoL: pain (85.2%) and fatigue (74.1%). The primary treatment expectation was achieving remission (40.7%), followed by extended life expectancy (14.8%). Patients most often defined meaningful change as improvement in symptoms (70.4%) and return to normalcy (40.7%). The percentage of patients reporting symptoms (pain, fatigue, bone fracture, gastrointestinal, neuropathy, and weakness) decreased from 85.2% to 22.2% across symptom types at baseline to 29.2% to 0% on Day 184 after cilta-cel. Improved symptoms and positive sentiments corresponded with improved perception of overall health status and reduced pain level, respectively. Most patients reported that their expectations of cilta-cel treatment had been met (70.8%) or exceeded (20.8%) at Day 184, and 70.8% of patients considered cilta-cel therapy better than their previous treatments. CONCLUSION: Overall HRQoL improvements and qualitative interviews showed cilta-cel met patient expectations of treatment and suggest the long treatment-free period also contributed to positive sentiments.

Ciltacabtagene Autoleucel, an Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up.

PURPOSE: CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up [MFU] approximately 28 months), including analyses of high-risk patient subgroups. METHODS: Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee. RESULTS: At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel-related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report. CONCLUSION: At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.

Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma.

BACKGROUND: G protein-coupled receptor, family C, group 5, member D (GPRC5D) is an orphan receptor expressed in malignant plasma cells. Talquetamab, a bispecific antibody against CD3 and GPRC5D, redirects T cells to mediate killing of GPRC5D-expressing myeloma cells. METHODS: In a phase 1 study, we evaluated talquetamab administered intravenously weekly or every other week (in doses from 0.5 to 180 µg per kilogram of body weight) or subcutaneously weekly, every other week, or monthly (5 to 1600 µg per kilogram) in patients who had heavily pretreated relapsed or refractory multiple myeloma that had progressed with established therapies (a median of six previous lines of therapy) or who could not receive these therapies without unacceptable side effects. The primary end points - the frequency and type of dose-limiting toxic effects (study part 1 only), adverse events, and laboratory abnormalities - were assessed in order to select the recommended doses for a phase 2 study. RESULTS: At the data-cutoff date, 232 patients had received talquetamab (102 intravenously and 130 subcutaneously). At the two subcutaneous doses recommended for a phase 2 study (405 µg per kilogram weekly [30 patients] and 800 µg per kilogram every other week [44 patients]), common adverse events were cytokine release syndrome (in 77% and 80% of the patients, respectively), skin-related events (in 67% and 70%), and dysgeusia (in 63% and 57%); all but one cytokine release syndrome event were of grade 1 or 2. One dose-limiting toxic effect of grade 3 rash was reported in a patient who had received talquetamab at the 800-µg dose level. At median follow-ups of 11.7 months (in patients who had received talquetamab at the 405-µg dose level) and 4.2 months (in those who had received it at the 800-µg dose level), the percentages of patients with a response were 70% (95% confidence interval [CI], 51 to 85) and 64% (95% CI, 48 to 78), respectively. The median duration of response was 10.2 months and 7.8 months, respectively. CONCLUSIONS: Cytokine release syndrome, skin-related events, and dysgeusia were common with talquetamab treatment but were primarily low-grade. Talquetamab induced a substantial response among patients with heavily pretreated relapsed or refractory multiple myeloma. (Funded by Janssen Research and Development; MonumenTAL-1 ClinicalTrials.gov number, NCT03399799.).

Health-related quality of life in patients given ciltacabtagene autoleucel for relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b-2, open-label study.

BACKGROUND: CARTITUDE-1 is a phase 1b-2 study evaluating ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma. Primary efficacy outcomes have previously been reported. Here, we report health-related quality of life (HRQOL) secondary outcomes evaluated using patient-reported outcomes. METHODS: This single-arm, open-label, phwase 1b-2 study was done at 16 centres in the USA. Patients were aged 18 years or older with diagnosis of multiple myeloma and Eastern Cooperative Oncology Group performance status of 1 or less with three or more previous lines of therapy, or were double refractory to a proteasome inhibitor and immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR+ T cells per kg) was administered 5-7 days after lymphodepletion. Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core 30-item, pre-specified items from the EORTC myeloma module, and EuroQol five-dimensional descriptive system questionnaire. Clinically meaningful changes in patient-reported outcomes were defined by anchor-based minimally important differences. This trial is registered with ClinicalTrials.gov, NCT03548207. This trial is completed but feeding into a long-term follow-up study. FINDINGS: Between July 16, 2018, and Oct 7, 2019, 78 patients were enrolled and underwent apheresis in phase 2 of the study. 68 patients were treated (43 [63%] male, 49 [72%] White), and their patient-reported outcomes assessed (median follow-up 16·9 months, IQR 15·7-17·5). After infusion, a transient decline was observed, followed by improvements in global health status (mean change from baseline to day 464 +8·0 points, SD 20·9), physical (+4·6 points, 21·1), and emotional functional scales (+1·9 points, 23·7) over time, and declines for symptom-based scores (-14·1 pain, SD 31·5 and -15·4 fatigue; SD 29·5), indicating improved patient HRQOL following treatment with cilta-cel. INTERPRETATION: These durable HRQOL improvements are consistent with clinical findings, in which a single cilta-cel infusion led to substantial and durable responses in heavily pre-treated patients with relapsed or refractory multiple myeloma. These results support the use of cilta-cel in patients with relapsed or refractory multiple myeloma. FUNDING: Janssen Research & Development and Legend Biotech USA.

Meta-analysis of ciltacabtagene autoleucel versus physician's choice therapy for the treatment of patients with relapsed or refractory multiple myeloma.

Objective: In the absence of head-to-head trials, indirect treatment comparisons (ITCs) between ciltacabtagene autoleucel (cilta-cel; in CARTITUDE-1) and treatments used in real-world clinical practice (physician's choice of treatment [PCT]), were previously conducted. We conducted multiple meta-analyses using available ITC data to consolidate the effectiveness of cilta-cel versus PCT for patients with triple-class exposed relapsed or refractory multiple myeloma (RRMM).Methods: Five ITCs were assessed for similarity to ensure robust comparisons using meta-analysis. Effectiveness outcomes were overall survival (OS), progression-free survival (PFS), time to next treatment (TTNT), and overall response rate (ORR). A robust variance estimator was used to account for the use of CARTITUDE-1 in each pairwise ITC. Analyses were conducted in both treated and enrolled populations of CARTITUDE-1.Results: Four ITCs were combined for evaluation of OS. Results were statistically significantly in favor of cilta-cel versus PCT in treated patients (hazard ratio [HR]: 0.24, 95% confidence interval [CI]: 0.22-0.26). Three ITCs were combined for evaluation of PFS and TTNT. Cilta-cel reduced the risk of progression and receiving a subsequent treatment by 80% (HR: 0.20 [95% CI: 0.06, 0.70]) and 83% (HR: 0.17 [95% CI: 0.12, 0.26]), respectively. Three ITCs were combined for evaluation of ORR. Cilta-cel increased the odds of achieving an overall response by 86-times versus PCT in treated patients. Findings were consistent in the enrolled populations and across sensitivity analyses.Conclusions: Evaluating multiple indirect comparisons, cilta-cel demonstrated a significantly superior advantage over PCT, highlighting its effectiveness as a therapy in patients with triple-class exposed RRMM.

Comparative effectiveness of ciltacabtagene autoleucel in CARTITUDE-1 versus physician's choice of therapy in the Flatiron Health multiple myeloma cohort registry for the treatment of patients with relapsed or refractory multiple myeloma.

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a novel chimeric antigen receptor T-cell therapy that is being evaluated in the CARTITUDE-1 trial (NCT03548207) in patients with relapsed or refractory multiple myeloma (RRMM) who received as part of their previous therapy an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody (i.e., triple-class exposed). Given the absence of a control arm in CARTITUDE-1, this study assessed the comparative effectiveness of cilta-cel and physician's choice of treatment (PCT) using an external real-world control arm from the Flatiron Health multiple myeloma cohort registry. Methods: Given the availability of individual patient data for cilta-cel from CARTITUDE-1 and PCT in Flatiron, inverse probability of treatment weighting was used to adjust for unbalanced baseline covariates of prognostic significance: refractory status, cytogenetic profile, International Staging System stage, time to progression on last regimen, number of prior lines of therapy, years since diagnosis, and age. Comparative effectiveness was estimated for progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). A range of sensitivity analyses were conducted. Results: Baseline characteristics were similar between the two cohorts after propensity score weighting. Patients with cilta-cel had improved PFS (HR: 0.18 [95% CI: 0.12, 0.27; p < 0.0001]), TTNT (HR: 0.15 [95% CI: 0.09, 0.22; p < 0.0001]), and OS (HR: 0.25 [95% CI: 0.13, 0.46; p < 0.0001]) versus PCT. Cilta-cel treatment benefit was robust and consistent across all sensitivity analyses. Conclusion: Cilta-cel demonstrated significantly superior effectiveness over PCT for all outcomes, highlighting its potential as an effective therapy in patients with triple-class exposed RRMM.

Matching-Adjusted Indirect Treatment Comparison to Assess the Comparative Efficacy of Ciltacabtagene Autoleucel in CARTITUDE-1 Versus Belantamab Mafodotin in DREAMM-2, Selinexor-Dexamethasone in STORM Part 2, and Melphalan Flufenamide-Dexamethasone in HORIZON for the Treatment of Patients With Triple-Class Exposed Relapsed or Refractory Multiple Myeloma.

INTRODUCTION: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel; CARTITUDE-1), a chimeric antigen receptor (CAR)-T-cell therapy, versus 3 non-CAR-T therapies (belantamab mafodotin [DREAMM-2], selinexor plus dexamethasone [STORM Part 2], and melphalan flufenamide plus dexamethasone [HORIZON]), each with distinct mechanisms of action, for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody. PATIENTS AND METHODS: Pairwise matching-adjusted indirect treatment comparisons (MAICs) were conducted using patient-level data for cilta-cel from CARTITUDE-1 and summary level data for each comparator (2.5 mg/kg cohort in DREAMM-2, modified intention-to-treat population in STORM Part 2, and triple-class refractory patients in HORIZON). Treated patients from CARTITUDE-1 who satisfied the eligibility of the comparator trial were included. MAICs adjusted for imbalances in important prognostic factors between CARTITUDE-1 and the comparator populations. Comparative efficacy of cilta-cel versus each therapy was estimated for overall response rate, complete response or better rate, progression-free survival, and overall survival. RESULTS: After adjustment, patients treated with cilta-cel demonstrated at least a 3.1-fold and at least a 10.3-fold increase in the likelihood of achieving an overall response or complete response or better, respectively, at least a 74% reduction in the risk of disease progression or death, and at least a 47% reduction in the risk of death. These results were statistically significant. CONCLUSION: Cilta-cel showed improved efficacy over each comparator for all outcomes, demonstrating its potential as an efficacious treatment for patients with triple-class exposed RRMM.

Comparison of Cilta-cel, an Anti-BCMA CAR-T Cell Therapy, Versus Conventional Treatment in Patients With Relapsed/Refractory Multiple Myeloma.

BACKGROUND: In the single-arm, phase 1b/2 CARTITUDE-1 study, ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen chimeric antigen receptor T-cell (CAR-T) therapy, showed encouraging efficacy in US patients with multiple myeloma (MM) who previously received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 monoclonal antibody (triple-class exposed). PATIENTS AND METHODS: A dataset of US patients refractory to an anti-CD38 monoclonal antibody (MAMMOTH) was used to identify patients who would meet eligibility for CARTITUDE-1 and received subsequent non-CAR-T therapy. The intent-to-treat (ITT) population in CARTITUDE-1 included patients who underwent apheresis (N = 113); the modified ITT (mITT) population was the subset who received cilta-cel (n = 97). Corresponding populations were identified from the MAMMOTH dataset: ITT population (n = 190) and mITT population of patients without progression/death within 47 days (median apheresis-to-cilta-cel infusion time) from onset of therapy (n = 122). Using 1:1 nearest neighbor propensity score matching to control for selected baseline covariates, 95 and 69 patients in CARTITUDE-1 ITT and mITT populations, respectively, were matched to MAMMOTH patients. RESULTS: In ITT cohorts of CARTITUDE-1 vs. MAMMOTH, improved overall response rate (ORR; 84% vs. 28% [P < .001]) and longer progression-free survival (PFS; hazard ratio [HR], 0.11 [95% confidence interval (CI), 0.05-0.22]) and overall survival (OS; HR, 0.20 [95% CI, 0.10-0.39]) were observed. Similar results were seen in mITT cohorts of CARTITUDE-1 vs. MAMMOTH (ORR: 96% vs. 30% [P < .001]; PFS: HR, 0.02 [95% CI, 0.01-0.14]; OS: HR, 0.05 [95% CI, 0.01-0.22]) and with alternative matching methods. CONCLUSION: Cilta-cel yielded significantly improved outcomes versus real-world therapies in triple-class exposed patients with relapsed/refractory MM.

Comparative Efficacy of Ciltacabtagene Autoleucel in CARTITUDE-1 vs Physician's Choice of Therapy in the Long-Term Follow-Up of POLLUX, CASTOR, and EQUULEUS Clinical Trials for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma.

BACKGROUND AND OBJECTIVE: Ciltacabtagene autoleucel (cilta-cel) is a novel agent being investigated in the single-arm CARTITUDE-1 trial (NCT03548207) for patients with relapsed or refractory multiple myeloma who are triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody. The objective of this study was to evaluate the comparative efficacy of cilta-cel vs physician's choice of treatment, as no head-to-head trials have been conducted. METHODS: An external control arm for CARTITUDE-1 was created from patients in the long-term follow-up for three clinical trials of daratumumab (POLLUX, CASTOR, and EQUULEUS) who satisfied the eligibility criteria of CARTITUDE-1. These patients received physician's choice of treatment following the discontinuation of study drugs. Inverse probability of treatment weighting was used to align the external control and CARTITUDE-1 populations on important baseline characteristics. Overall response rate, complete response or better rate, progression-free survival, time to next treatment, and overall survival were assessed. Several sensitivity analyses were conducted. RESULTS: After propensity score weighting, baseline characteristics were comparable between cohorts. Patients showed improved results with cilta-cel vs physician's choice of treatment: overall response rate (relative risk: 2.95 [95% confidence interval (CI) 2.27, 3.84; p < 0.0001]), complete response or better (relative risk: 111.70 [95% CI 29.08, 429.06; p < 0.0001]), progression-free survival (hazard ratio [HR]: 0.24 [95% CI 0.15, 0.37; p < 0.0001]), time to next treatment (HR: 0.14 [95% CI 0.09, 0.22; p < 0.0001]), and overall survival (HR: 0.21 [95% CI 0.13, 0.35; p < 0.0001]). Results were consistent across all sensitivity analyses. CONCLUSIONS: Cilta-cel showed superior efficacy compared with physician's choice of treatment, making it a promising new treatment option for patients with triple-class exposed relapsed or refractory multiple myeloma.