Cilta-cel, a BCMA-targeting CAR-T therapy for patients with multiple myeloma.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), a BCMA-targeting CAR-T therapy, is approved in the United States and Europe for patients with relapsed/refractory multiple myeloma (RRMM) and ≥1 prior line of therapy (LOT), including a proteasome inhibitor and an immunomodulatory drug, and are lenalidomide refractory. AREAS COVERED: We examine recent long-term data in heavily pretreated RRMM (LEGEND-2, CARTITUDE-1) and earlier LOTs (CARTITUDE-4) compared with standard therapy and discuss the rationale for investigating cilta-cel as frontline therapy for transplant-eligible and transplant-ineligible patients (CARTITUDE-5, CARTITUDE-6). EXPERT OPINION: CAR-T therapies can improve outcomes for patients with MM across different LOTs. CARTITUDE-1 and CARTITUDE-4 have set a new bar for efficacy, with median PFS of 34.9 months in heavily pretreated patients (CARTITUDE-1) and a 74% relative risk reduction for progression/death versus standard care in patients with 1-3 prior LOTs (CARTITUDE-4), with manageable safety. Response rates were consistent between the two studies: 98% in CARTITUDE-1 and approaching 100% for infused patients in CARTITUDE-4. Cilta-cel could be a key treatment choice for patients with RRMM after first LOT. Clinical trials investigating frontline cilta-cel therapy will provide valuable insights into optimizing treatment pathways with the aim to potentially cure MM.

Phase 1 study combining elotuzumab with autologous stem cell transplant and lenalidomide for multiple myeloma.

BACKGROUND: Autologous stem cell transplantation (ASCT) after induction therapy improves disease-free survival for patients with multiple myeloma (MM). While the goal of ASCT is to render a minimal disease state, it is also associated with eradication of immunosuppressive cells, and we hypothesize that early introduction of immunotherapy post-ASCT may provide a window of opportunity to boost treatment efficacy. METHODS: We conducted a phase 1 clinical trial to investigate the application of autologous lymphocyte infusion and anti-SLAMF7 monoclonal antibody, elotuzumab, after ASCT in patients with newly diagnosed MM previously treated with induction therapy. In addition to CD34+ stem cells, peripheral blood mononuclear cells were harvested prior to transplant and infused on day 3 after stem cell infusion to accelerate immune reconstitution and provide autologous natural killer (NK) cells that are essential to the mechanism of elotuzumab. Elotuzumab was administered starting on day 4 and then every 28 days after until 1 year post-ASCT. Cycles 4-12 were administered with standard-of-care lenalidomide maintenance. RESULTS: All subjects were evaluated for safety, and 13 of 15 subjects completed the treatment protocol. At 1 year post-ASCT, the disease status of enrolled subjects was as follows: five stringent complete responses, one complete response, six very good partial responses, one partial response, and two progressive diseases. The treatment plan was well tolerated, with most grade 3 and 4 AEs being expected hematologic toxicities associated with ASCT. Correlative analysis of the immune microenvironment demonstrated a trend toward reduced regulatory T cells during the first 3 months post-transplant followed by an increase in NK cells and monocytes in patients achieving a complete remission. CONCLUSIONS: This phase 1 clinical trial demonstrates that early introduction of immunotherapy after ASCT is well tolerated and shows promising disease control in patients with MM, accompanied by favorable changes in the immune microenvironment. TRIAL REGISTRATION NUMBER: NCT02655458.

Optimizing the CAR T-Cell Therapy Experience in Multiple Myeloma: Clinical Pearls From an Expert Roundtable.

Chimeric antigen receptor T-cell (CAR-T) therapies offer substantial advancement in the treatment of multiple myeloma (MM). However, the CAR-T therapy process involves complex decision-making that is informed by many variables. This review aims to provide an overview of the patient selection and administration process for CAR-T therapy for MM from the perspective of experienced healthcare providers (HCPs), including considerations for each step in the CAR-T therapy process. Referring HCPs should initiate conversations with HCPs at CAR-T capable centers earlier in the treatment journey, even before patients are eligible for CAR-T therapy, particularly for patients from underserved populations and patients with high-risk disease, to ensure adequate time for logistical planning and patient education. Patient selection for CAR-T therapy may be guided by factors such as performance status, rate of disease progression, and logistical considerations. Some anticancer therapies may affect T-cell fitness and therefore impact CAR-T manufacturing and patient outcomes; however, additional research is needed to confirm this in MM. Bridging therapies should be tailored to the needs of the patient and ideally halted 1 week or longer before CAR-T infusion, contingent upon the agent(s) used. Lymphodepletion regimens may need to be modified for patients with renal insufficiency. Collaboration with HCPs at both the treating and referring centers is important to optimize coordinated care of patients. Collaboration with and guidance from experienced HCPs throughout patient selection, referral, and CAR-T administration is instrumental in optimizing patient outcomes as access to CAR-T therapies expands.

Cellular Mass Response to Therapy Correlates With Clinical Response for a Range of Malignancies.

PURPOSE: Cancer patients with advanced-stage disease have poor prognosis, typically having limited options for efficacious treatment, and genomics-based therapy guidance continues to benefit only a fraction of patients. Next-generation ex vivo approaches, such as cell mass-based response testing (MRT), offer an alternative precision medicine approach for a broader population of patients with cancer, but validation of clinical feasibility and potential impact remain necessary. MATERIALS AND METHODS: We evaluated the clinical feasibility and accuracy of using live-cell MRT to predict patient drug sensitivity. Using a unified measurement workflow with a 48-hour result turnaround time, samples were subjected to MRT after treatment with a panel of drugs in vitro. After completion of therapeutic course, clinical response data were correlated with MRT-based predictions of outcome. Specimens were collected from 104 patients with solid (n = 69) and hematologic (n = 35) malignancies, using tissue formats including needle biopsies, malignant fluids, bone marrow aspirates, and blood samples. Of the 81 (78%) specimens qualified for MRT, 41 (51%) patients receiving physician-selected therapies had treatments matched to MRT. RESULTS: MRT demonstrated high concordance with clinical responses with an odds ratio (OR) of 14.80 (P = .0003 [95% CI, 2.83 to 102.9]). This performance held for both solid and hematologic malignances with ORs of 20.67 (P = .0128 [95% CI, 1.45 to 1,375.57]) and 8.20 (P = .045 [95% CI, 0.77 to 133.56]), respectively. Overall, these results had a predictive accuracy of 80% (P = .0026 [95% CI, 65 to 91]). CONCLUSION: MRT showed highly significant correlation with clinical response to therapy. Routine clinical use is technically feasible and broadly applicable to a wide range of samples and malignancy types, supporting the need for future validation studies.

Prevalence and impact of diabetes on survival of patients with multiple myeloma in different racial groups.

ABSTRACT: Multiple myeloma (MM) is twice as common in Black individuals compared with in White individuals, and diabetes mellitus (DM) disproportionately affects Black patients. Although numerous studies have shown a correlation between DM and MM, this has not been studied in the context of race and in vivo mechanisms. We conducted a retrospective clinical study of 5383 patients with MM of which 15% had DM (White, 12% and Black, 25%). Multivariable Cox models showed reduced overall survival (OS) for patients with DM (hazard ratio, 1.27; 95% confidence interval, 1.11-1.47; P < .001). This appeared to be driven by a marked difference in OS between White patients with and without DM but not in Black patients. In contrast, obesity was associated with better OS in Black patients but not in White patients. To complement this analysis, we assessed MM growth in a genetically engineered immunocompromised nonobese diabetic (Rag1-/-/muscle creatinine kinase promoter expression of a human IGF1R [M] with a lysine [K] to arginine [R] point mutation) mouse model to evaluate the mechanisms linking DM and MM. MM.1S xenografts grew in more Rag1-/-/MKR mice and grew more rapidly in the Rag1-/-/MKR mice compared with in controls. Western blot analysis found that MM1.S xenografts from Rag1-/-/MKR mice had higher phosphorylated S6 ribosomal protein (Ser235/236) levels, indicating greater activation of the mammalian target of rapamycin pathway. Our study is, to our knowledge, the first to evaluate racial differences in DM prevalence and survival in MM, as well as the effect of DM on tumor growth in mouse models. Our results suggest that DM may contribute to the higher incidence of MM in Black patients; and to improve survival in MM, DM management cannot be ignored.

Real-World Utilization of Radiation Therapy in Multiple Myeloma: An Analysis of the Connect MM Registry.

PURPOSE: Radiation therapy (RT) is an important treatment modality for patients with multiple myeloma (MM). Although patients are living longer with MM, they are more likely to have comorbidities related to treatment, such as bone pain; however, RT can provide symptom relief. To date, the characterization of patients who have received RT in the real-world setting has been limited. METHODS AND MATERIALS: The Connect® MM Registry is a large, US multicenter, prospective observational cohort study of adult patients with newly diagnosed MM from mostly community sites. RT utilization and outcomes were analyzed quarterly throughout treatment. Factors associated with RT use were identified via multivariable analysis. RESULTS: A total of 3011 patients were enrolled in the Connect MM Registry with 903 patients (30%) having received RT at any time. There was a significant difference (P < .05) in overall RT use among patients with an Eastern Cooperative Oncology Group performance status of 0 to 1 versus ≥2, International Staging System disease stage I/II versus III, a history of plasmacytoma or a novel agent in their first regimen, and any number of bone lesions or severe osteoporosis/fracture. RT use was associated with having bone lesions or severe osteoporosis (vs not having bone lesions). Additionally, RT use was associated with ethnicity (Hispanic vs not) and Connect MM Registry cohort (cohort 1 [enrolled 2009-2011] vs 2 [enrolled 2012-2016]). In the 6 months before death, increased RT use was associated with increasing number of treatment lines (P < .0001) and high- versus standard-risk disease (per International Myeloma Working Group criteria; P = .0028). CONCLUSIONS: Real-world results from the Connect MM Registry show RT is frequently used and is associated with clinical factors, including performance status and disease stage. Earlier in MM diagnosis, RT may be used as an adjunct to palliate symptoms or delay systemic therapy. Toward the end of life, RT is more frequently used for palliation when treatment options are often limited.

Cellular mechanisms associated with sub-optimal immune responses to SARS-CoV-2 bivalent booster vaccination in patients with Multiple Myeloma.

BACKGROUND: The real-world impact of bivalent vaccines for wild type (WA.1) and Omicron variant (BA.5) is largely unknown in immunocompromised patients with Multiple Myeloma (MM). We characterize the humoral and cellular immune responses in patients with MM before and after receiving the bivalent booster, including neutralizing assays to identify patterns associated with continuing vulnerability to current variants (XBB1.16, EG5) in the current post-pandemic era. METHODS: We studied the humoral and cellular immune responses before and after bivalent booster immunization in 48 MM patients. Spike binding IgG antibody levels were measured by SARS-CoV-2 spike binding ELISA and neutralization capacity was assessed by a SARS-CoV-2 multi-cycle microneutralization assays to assess inhibition of live virus. We measured spike specific T-cell function using the QuantiFERON SARS-CoV-2 (Qiagen) assay as well as flow-cytometry based T-cell. In a subset of 38 patients, high-dimensional flow cytometry was performed to identify immune cell subsets associated with lack of humoral antibodies. FINDINGS: We find that bivalent vaccination provides significant boost in protection to the omicron variant in our MM patients, in a treatment specific manner. MM patients remain vulnerable to newer variants with mutations in the spike portion. Anti-CD38 and anti-BCMA therapies affect the immune machinery needed to produce antibodies. INTERPRETATION: Our study highlights varying immune responses observed in MM patients after receiving bivalent COVID-19 vaccination. Specifically, a subgroup of MM patients undergoing anti-CD38 and anti-BCMA therapy experience impairment in immune cells such DCs, B cells, NK cells and TFH cells, leading to an inability to generate adequate humoral and cellular responses to vaccination. FUNDING: National Cancer Institute (National Institutes of Health), National Institute of Allergy and Infectious Diseases (National Institutes of Health), NCI Serological Sciences Network for COVID-19 (SeroNet) and The Icahn School of Medicine at Mount Sinai.

Association of Selinexor Dose Reductions With Clinical Outcomes in the BOSTON Study.

BACKGROUND: Dose modifications in response to adverse events (AEs) can maintain tumor response and improve therapy tolerability. We conducted a post-hoc analysis of the efficacy and safety of reduced selinexor doses in the BOSTON trial (NCT03110562). PATIENTS AND METHODS: Efficacy, safety, and quality of life (QoL) in 195 patients with relapsed/refractory multiple myeloma randomized to once-weekly (QW) selinexor (100 mg), QW subcutaneous bortezomib (1.3 mg/m2), and twice-weekly dexamethasone (20 mg) were compared between patients with dose reductions and those without. RESULTS: In total, 126 patients (65%) had selinexor dose reductions (median dose 71.4 mg/wk). In patients with dose reductions versus those without median progression-free survival was 16.6 months (95% CI 12.9-not evaluable [NE]) versus 9.2 months [95% CI 6.8-15.5]), overall response rate was 81.7% (95% CI 73.9-88.1%) versus 66.7% (95% CI 54.3-77.6%), ≥very good partial response was (51.6% [95% CI 42.5-60.6%] vs. 31.9% [95% CI 21.2-44.2]), median duration of response was not reached (95% CI 13.8-NE) versus 12.0 months (95% CI 8.3-NE), and time to next treatment was 22.6 months (95% CI 14.6-NE) versus 10.5 months (95% CI 6.3-18.2). Mean best change from baseline on the EORTC QLQ-C30 Global Health Status/QoL scale was 10.0 ± 20.5 versus 4.0 ± 20.9. Duration-adjusted AE rates that were lower after selinexor dose reduction included thrombocytopenia (62.5% before vs. 47.6% after), nausea (31.6% vs. 7.3%), fatigue (28.1% vs. 9.9%), decreased appetite (21.5% vs. 6.4%), anemia (17.9% vs. 10.3%), and diarrhea (12.9% vs. 5.2%). CONCLUSION: Appropriate dose reductions in response to AEs of the 100 mg selinexor starting dose in the BOSTON study were associated with improved efficacy, reduced AE rates and improved QoL.

IVIg Use Associated with Ten-Fold Reduction of Serious Infections in Multiple Myeloma Patients Treated with Anti-BCMA Bispecific Antibodies.

BCMA-targeted bispecific antibodies (BiAb) are efficacious in relapsed/refractory multiple myeloma; however, serious infections have emerged as important toxicities. In this retrospective study, we characterized all infections and their risk factors, and evaluated the impact of infection prophylaxis in patients treated with BCMA-targeted BiAbs. Among 37 patients, 15 (41%) experienced a grade 3-5 infection, with two infection-related deaths during deep remissions. Most (84%) infections occurred during disease remissions. The cumulative probability of grade 3-5 infection increased over time with no plateau. Among responders (n = 26), profound hypogammaglobulinemia occurred in 100% and continued throughout the entire duration of treatment. During periods when patients were receiving intravenous immunoglobulin (IVIg), the rate of grade 3-5 infections was 90% lower than during observation (incidence rate ratio, 0.10; 95% confidence interval, 0.01-0.80; P = 0.0307). No other risk factors for infection were identified. This study demonstrates that profound hypogammaglobulinemia is universal with BCMA-targeted BiAbs, with intravenous immunoglobulin potentially abrogating most of the infection risk. SIGNIFICANCE: To the best of our knowledge, this is the first study to comprehensively analyze risk factors and mitigation strategies to prevent infections in myeloma patients receiving anti-BCMA bispecific antibodies. Profound and prolonged hypogammaglobulinemia was universal among responders, while immunoglobulin replacement was associated with 90% lower rates of grade 3-5 infections. See related commentary by Garfall and Stadtmauer, p. 427 . This article is featured in Selected Articles from This Issue, p. 419.

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 .

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).

Extrapolation of Survival Data Using a Bayesian Approach: A Case Study Leveraging External Data from Cilta-Cel Therapy in Multiple Myeloma.

INTRODUCTION: Extrapolating long-term overall survival (OS) from shorter-term clinical trial data is key to health technology assessment in oncology. However, extrapolation using conventional methods is often subject to uncertainty. Using ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy for multiple myeloma, we used a flexible Bayesian approach to demonstrate use of external longer-term data to reduce the uncertainty in long-term extrapolation. METHODS: The pivotal CARTITUDE-1 trial (NCT03548207) provided the primary efficacy data for cilta-cel, including a 12-month median follow-up snapshot of OS. Longer-term (48-month median follow-up) survival data from the phase I LEGEND-2 study (NCT03090659) were also available. Twelve-month CARTITUDE-1 OS data were extrapolated in two ways: (1) conventional survival models with standard parametric distributions (uninformed), and (2) Bayesian survival models whose shape prior was informed from 48-month LEGEND-2 data. For validation, extrapolations from 12-month CARTITUDE-1 data were compared with observed 28-month CARTITUDE-1 data. RESULTS: Extrapolations of the 12-month CARTITUDE-1 data using conventional uninformed parametric models were highly variable. Using informative priors from the 48-month LEGEND-2 dataset, the ranges of projected OS at different timepoints were consistently narrower. Area differences between the extrapolation curves and the 28-month CARTITUDE-1 data were generally lower in informed Bayesian models, except for the uninformed log-normal model, which had the lowest difference. CONCLUSIONS: Informed Bayesian survival models reduced variation of long-term projections and provided similar projections as the uninformed log-normal model. Bayesian models generated a narrower and more plausible range of OS projections from 12-month data that aligned with observed 28-month data. TRIAL REGISTRATION: CARTITUDE-1 ClinicalTrials.gov identifier, NCT03548207. LEGEND-2 ClinicalTrials.gov identifier, NCT03090659, registered retrospectively on 27 March 2017, and ChiCTR-ONH-17012285.

What Affects Treatment Underuse in Multiple Myeloma in the United States: A Qualitative Study.

BACKGROUND: Multiple myeloma (MM) is the second most common hematologic malignancy. African Americans are more likely than Whites to be diagnosed with and die of MM, but they experience the same survival times in clinical trials, suggesting that differences in survival may be attributed to differences in receipt of treatment or differences in access to new treatments. We undertook this study to identify the reasons and needs underlying disparities in treatment among patients diagnosed with MM. METHODS: We conducted in-depth interviews in 2019-2020 with patients diagnosed with MM between 2010 and 2014 who were identified as eligible for transplant and maintenance therapy and having experienced delays in or underuse of treatment for MM. Underuse was defined as the lack of a particular treatment that the patient was eligible to receive, not being transplanted if eligible, and/or not receiving maintenance therapy. Underuse included patients' decision to delay harvest or autologous stem cell transplant (ASCT) for the time being and return to the decision in the future. All interviews were audio-recorded and transcribed verbatim. Four investigators independently coded transcripts through inductive analysis to assess reasons for treatment decisions. RESULTS: Of the 29 patients interviewed, 68% experienced treatment underuse: 21% self-identified as African American, 5% as Hispanic, 10% as mixed race, 57% as White, and 16% as Asian. There were no racial differences in reasons for underuse or delay. Themes relating to treatment underuse included: perceived pros and cons of treatment, including potential harm or lack thereof in delaying treatment; physician recommendations; and personal agency. CONCLUSION: Patients' decision making, delays, and underuse of MM treatment are influenced by social, personal, medical, and contextual factors. Patients consider their relationship with their physician to be one of the most significant driving forces in their decisions and treatment plans.

Immune Reconstitution and Vaccinations in Multiple Myeloma: A Report From the 19th International Myeloma Society Annual Workshop.

Given the significance of the immune system and the important role of therapies within the context of the immune system in plasma cell disorders, the International Myeloma Society annual workshop convened a session dedicated to this topic. A panel of experts covered various aspects of immune reconstitution and vaccination. The top oral presentations were highlighted and discussed. This is a report of the proceedings.

Component Costs of CAR-T Therapy in Addition to Treatment Acquisition Costs in Patients with Multiple Myeloma.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), is a B-cell maturation antigen-directed, genetically modified autologous chimeric antigen receptor T-cell (CAR-T) immunotherapy. It is indicated for treatment for adult patients with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The objective of this study was to estimate the per-patient US commercial healthcare costs related to cilta-cel (CARVYKTI®) CAR-T therapy (i.e., costs separate from cilta-cel therapy acquisition) for patients with RRMM. METHODS: US prescribing information for cilta-cel, publicly available data, and published literature were used with clinician input to identify the cost components and unit costs associated with administration of cilta-cel. Cost components included apheresis, bridging therapy, conditioning therapy, administration, and postinfusion monitoring for 1 year of follow-up. Adverse event (AE) management costs for all grades of cytokine release syndrome and neurologic toxicities, and additional AEs grade ≥ 3 occurring in > 5% of patients were included in the analysis. RESULTS: The estimated per-patient average costs of cilta-cel CAR-T therapy administered exclusively in an inpatient setting, excluding cilta-cel therapy acquisition costs, totaled US$160,933 over a 12 month period. Costs assuming different proportions of inpatient/outpatient administration (85%/15% and 70%/30%) were US$158,095 and US$155,257, respectively. CONCLUSION: Cost estimates from this analysis, which disaggregates CAR-T therapy costs, provide a comprehensive view of the cost components of CAR-T therapy that can help healthcare decision-makers make informed choices regarding the use of cilta-cel. Real-world costs may differ with improved AE prevention and mitigation strategies.

Recent Advances in the Use of Chimeric Antigen Receptor-Expressing T-Cell Therapies for Treatment of Multiple Myeloma.

INTRODUCTION: Chimeric antigen receptor T cell (CAR-T) therapies have revolutionized the treatment paradigm for heavily pretreated B-cell malignancies such as large B-cell lymphoma. There is a major unmet need for effective treatments for heavily pretreated relapsed/refractory multiple myeloma (RRMM), for which many CAR-T therapies are under active clinical investigation. Goal of the review: This review provides an overview of recently updated clinical trial data and indirect treatment comparison analyses regarding two clinically advanced CAR-T therapies, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). DISCUSSION: Recently presented data after prolonged follow-up periods for ide-cel (KarMMa) and cilta-cel (CARTITUDE-1) have demonstrated that both therapies have the potential to elicit responses in individuals with heavily pretreated RRMM. Indirect treatment comparisons between cilta-cel and ide-cel suggest cilta-cel is associated with deeper and more durable responses than ide-cel in triple class-exposed RRMM; however, these types of comparisons have limitations and direct head-to-head trials are needed to confirm these findings. Additional indirect treatment comparisons conducted separately for ide-cel and cilta-cel have demonstrated that these CAR-T therapies hold promise for substantial clinical benefit relative to currently available treatments for RRMM. Further considerations, including safety profiles and real-world treatment considerations, are also discussed. CONCLUSION: Data collected to date support CAR-T therapies holding substantial promise for patients with heavily pretreated RRMM relative to other currently available therapies. Additional real-world data will help provide further insights into the comparative efficacy and safety profiles of these treatments in RRMM as these treatments become more widely available.