Analysis of patient-reported experiences up to 2 years after receiving idecabtagene vicleucel (ide-cel, bb2121) for relapsed or refractory multiple myeloma: Longitudinal findings from the phase 2 KarMMa trial.

OBJECTIVE: To understand the long-term experience of patients receiving ide-cel chimeric antigen receptor T (CAR T) cell therapy for relapsed or refractory multiple myeloma in the pivotal phase 2 KarMMa trial. METHODS: This qualitative study analyzed semi-structured patient interviews 6-24 months after ide-cel infusion. Thematic analysis with quantitative and longitudinal analyses explored patient perceptions of ide-cel treatment experience, advantages and disadvantages, and long-term health-related quality of life impact. Patient journeys were developed from narrative analysis of perceived treatment benefits with known remission length. RESULTS: Interviews with 45 patients 6-24 months postinfusion were analyzed; all reported ≥ 1 ide-cel treatment advantage, most often related to efficacy (n = 42/45, 93%), few or no side effects (n = 35/45, 78%), and avoidance of other treatments (n = 34/45, 76%). Patients generally reported 6-month improvements in physical health, functioning, emotional well-being, social life, and outlook on the future; these improvements mostly remained "stable" through 18 and 24 months. The most common patient journeys comprised physical, functioning, or emotional benefit with remission < 2 years. CONCLUSIONS: Longitudinal analysis of patient experiences showed sustained benefits and preference for ide-cel up to 24 months after treatment. Trial Registration Number and Date: NCT03361748. December 5, 2017.

Patient experience before and after treatment with idecabtagene vicleucel (ide-cel, bb2121): qualitative analysis of patient interviews in the KarMMa trial.

OBJECTIVE: To understand the experience of patients with relapsed and refractory multiple myeloma (RRMM) receiving idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, in the pivotal, phase 2 KarMMa trial. METHODS: Optional semi-structured interviews before leukapheresis (pre-treatment) captured expectations and after ide-cel infusion (1, 2, and 3 months post-treatment), assessed treatment experience, ide-cel advantages/disadvantages, and health and well-being. In a mixed-method analysis, treatment experiences were categorized by clinical response status, health and well-being, and self-reported recovery after infusion. RESULTS: Pre-treatment interviews indicated unmet treatment needs. In post-treatment interviews, most patients reported the positives of ide-cel outweighed negatives (69%, n = 27/39). Most common advantages of ide-cel were efficacy (18-64%), favorable side-effect profile (46-68%), and recovery time (13-18%); most common disadvantages were related to side effects (13-20%). When analyzed by clinical response, patients most often had stringent complete or very good partial response and improved health and well-being with mild or severe recovery from the infusion (27/58, 47%). Most patients with minimal clinical response reported mild infusion recovery (5/6, 83%). CONCLUSIONS: Patient interviews before ide-cel treatment showed unmet needs in triple-class exposed RRMM. Post-treatment experiences generally favored ide-cel versus previously received treatments.

Health-related quality of life with idecabtagene vicleucel in relapsed and refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, showed deep, durable responses in patients with triple-class exposed, relapsed and refractory multiple myeloma (RRMM) in the phase 2 KarMMa (Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma) trial. We assessed health-related quality of life (HRQoL) among KarMMa patients. The European Organization for Research and Treatment of Cancer Quality of Life C30 Questionnaire and its supplementary 20-item multiple myeloma module, as well as the EuroQol 5-dimension 5-level instrument, were administered at screening, baseline (≤72 hours before or same day as lymphodepletion), day of ide-cel treatment, and after ide-cel treatment. Mean changes from baseline that exceeded the predetermined threshold of minimally important difference were deemed clinically meaningful. The proportions of patients experiencing clinically meaningful changes in HRQoL were assessed using within-patient change thresholds. Time to stable improvement (≥2 consecutive visits with clinically meaningful HRQoL improvements) was analyzed by using the Kaplan-Meier method. A total of 126 (98%) of 128 patients treated with ide-cel were included in the HRQoL analysis. Pretreatment baseline RRMM burden was high and meaningfully worse than that in the age- and sex-weighted general population. Statistically significant and clinically meaningful improvements from baseline were observed by month 1 for pain (-8.9) and disease symptoms (-10.2), and by month 2 for fatigue (-7.2), physical functioning (6.1), cognitive functioning (6.7), and global health status/QoL (8.0). Clinically meaningful improvements in fatigue, pain, and physical functioning were most prominent at months 9, 12, and 18, respectively, and were sustained through 15 to 18 months after ide-cel treatment. For triple-class exposed patients with RRMM with a poor prognosis and few treatment options, a single ide-cel infusion provides early, sustained, statistically significant, and clinically meaningful improvements in HRQoL. This study was registered at Clinicaltrials.gov as #NCT03361748.

Treatment Patterns and Outcomes in Triple-Class Exposed Patients With Relapsed and Refractory Multiple Myeloma: Findings From the Multinational ITEMISE Study.

PURPOSE: Patients with relapsed and refractory multiple myeloma (RRMM) have a poor prognosis and limited treatment options after exposure to an immunomodulatory drug, proteasome inhibitor (PI), and anti-CD38 antibody (triple-class exposure [TCE]). However, current understanding about the management of these patients and associated health care resource use (HCRU) is limited outside the United States. The objective of the International Treatment pattern and resource use Evaluation for Multiple myeloma In a Study of triple-class Exposed patients (ITEMISE) study was to use a physician-developed survey fielded to hematologists across Europe and Canada to assess the treatment, management, HCRU, and end-of-life care for patients with RRMM after TCE. METHODS: The ITEMISE study used a 3-phase Delphi-like approach that consisted of in-depth interviews with 7 hematology experts; the development of a cross-sectional survey fielded to hematologists across Belgium, Canada, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland, and the United Kingdom from August to October 2020; and a final workshop of hematology experts to validate the pooled findings. Hematologists were asked to consider the management of patients in the first 3 treatment lines after TCE, including treatment options, treatment duration and outcomes, and frequency of outpatient visits and hospitalizations. FINDINGS: The survey was completed by 202 hematologists (60% from academic hospitals, 38% from other public hospitals, and 2% from private hospitals). Hematologists estimated that 55% of patients would receive active treatment after TCE, the equivalent of fourth-line treatment onward since diagnosis of multiple myeloma. Immunomodulatory drug, anti-CD38 antibody plus immunomodulatory drug, and PI-based regimens (received by 22.5%, 17.8%, and 15.1% of patients, respectively) were reported for first treatment strategy after TCE. Pomalidomide, daratumumab, lenalidomide, bortezomib, and carfilzomib were the most frequently selected antimyeloma agents. Associated outcomes of median overall survival, progression-free survival, and objective response rate for first treatment after TCE were estimated as 12 months, 4 months, and 40%, respectively. HCRU included outpatient visits and unplanned hospitalizations that were commonly reported during treatment after TCE. IMPLICATIONS: Findings indicate an intent to actively treat patients after TCE with a range of combination regimens frequently consisting of immunomodulatory drugs, PIs, and anti-CD38 antibodies, highlighting the lack of standard of care and suggesting a large clinical unmet need. Estimated clinical outcomes are consistent with data from US studies and indicate the poor prognosis for patients after TCE. Substantial HCRU is associated with management of patients after TCE across Europe and Canada, signifying a high patient and societal impact and a need for better treatment options to reduce this burden.

Supercritical fluid technology based large porous celecoxib-PLGA microparticles do not induce pulmonary fibrosis and sustain drug delivery and efficacy for several weeks following a single dose.

Although pulmonary dosing of large porous particles has been shown to sustain drug delivery for a few days, there are no reports on safety or long term delivery. In this study we prepared large porous poly(lactide-co-glycolide) (PLGA) microparticles of celecoxib using supercritical fluid pressure-quench technology and demonstrated 4.8-, 15.7-, and 2.1-fold greater drug levels in lung, bronchoalveolar lavage fluid (BAL), and plasma compared to conventional microparticles on day 21 after a single intratracheal dosing of dry powders in A/J mice. Porous particle based delivery was 50.2-, 95.5-, and 7.7-fold higher compared to plain drug in the lung, BAL, and plasma, respectively. Toxicity of the formulations was assessed on day 21 following a fibrosis assessment protocol in A/J mice. There was no significant change in lactate dehydrogenase (LDH), total protein, and total cell counts in the BAL, and soluble collagen levels in the lung tissue following particle or drug treatments. Lung histology indicated no significant hyperplasia, granuloma, or collagen deposition in the treated groups. Chemopreventive potential of celecoxib porous particles was assessed in a benzo[a]pyrene (B[a]P) induced lung cancer model in A/J mice, on day 60 following a single intratracheal dose with or without single intravenous paclitaxel/carboplatin treatment. The combination group was more effective than individual groups, with the inhibition of tumor multiplicity and reduction of vascular endothelial growth factor in the BAL being 70 and 58%, respectively. Thus, large porous celecoxib-PLGA microparticles prepared using supercritical fluid technology exhibited sustained drug delivery and anti-tumor efficacy, without causing any significant toxicity.

Intratracheal budesonide-poly(lactide-co-glycolide) microparticles reduce oxidative stress, VEGF expression, and vascular leakage in a benzo(a)pyrene-fed mouse model.

The purpose of this study was to determine whether intratracheally instilled polymeric budesonide microparticles could sustain lung budesonide levels for one week and inhibit early biochemical changes associated with benzo(a)pyrene (B[a]P) feeding in a mouse model for lung tumours. Polymeric microparticles of budesonide-poly (DL-lactide-co-glycolide) (PLGA 50:50) were prepared using a solvent evaporation technique and characterized for their size, morphology, encapsulation efficiency, and in-vitro release. The microparticles were administered intratracheally (i.t.) to B[a]P-fed A/J mice. At the end of one week drug levels in the lung tissue and bronchoalveolar lavage (BAL) were estimated using HPLC and compared with systemic (intramuscular) administration. In addition, in-vivo end points including malondialdehyde (MDA), glutathione (GSH), total protein levels and vascular endothelial growth factor (VEGF) in BAL, and VEGF and c-myc mRNA levels in the lung tissue were assessed at the end of one week following intratracheal administration of budesonide microparticles. Budesonide-PLGA microparticles (1-2 microm), with a budesonide loading efficiency of 69-94%, sustained in-vitro budesonide release for over 21 days. Compared with the intramuscular route, intratracheally administered budesonide-PLGA microparticles resulted in higher budesonide levels in the BAL and lung tissue. In-vivo, B[a]P-feeding increased BAL MDA, lung VEGF mRNA, lung c-myc mRNA, BAL total protein, and BAL VEGF levels by 60, 112, 71, 154, and 78%, respectively, and decreased BAL GSH by 62%. Interestingly, intratracheally administered budesonide-PLGA particles inhibited these biochemical changes. Thus, biodegradable budesonide microparticles sustained budesonide release and reduced MDA accumulation, GSH depletion, vascular leakage, and VEGF and c-myc expression in B[a]P-fed mice, indicating the potential of locally delivered sustained-release particles for inhibiting angiogenic factors in lung cancer.