Patient Outcome In Multiple Myeloma Research Articles

Comorbidities and survival of multiple myeloma patients diagnosed in Finland between 2000 and 2021.

Advances in treatment have improved the survival of multiple myeloma (MM) patients, but the disease remains incurable. Here, in this nationwide retrospective real-world evidence (RWE) study, we report the patient characteristics, incidence, overall survival outcomes, comorbidities, and healthcare resource utilization (HCRU) of all adult MM patients diagnosed between 2000 and 2021 in Finland. A total of 7070 MM patients and their 21,210 age-, sex- and region-matched controls were included in the analysis. The average MM incidence doubled from 4.11 to 8.33 per 100,000 people during the follow-up. The average age-standardized incidence also showed a significant increase over time (2.51 in 2000 to 3.53 in 2021). An increase in incidence was particularly seen in older population, indicative of improved diagnosis praxis. The median overall survival (mOS) of the MM patients and their matched controls was 3.6 and 15.6 years, respectively. The mOS of all MM patients increased significantly from 2.8 years (2000-2004) to 4.4 years (2017-2021) during the follow-up period. Distinctively, in patients who received autologous stem cell transplantation (ASCT), the mOS was 9.2 years, while in patients who did not receive ASCT, the mOS was only 2.7 years. MM patients showed more comorbidities at index and increased HCRU than their matched controls. The longer median survival and decreased risk of death indicate improved treatment outcomes in MM patients in Finland.

Unlocking hope: talquetamab in multiple myeloma treatment: a bispecific breakthrough targeting CD3 and GPRC5D

Multiple myeloma (MM) presents a significant global health burden, with disparities in incidence and outcomes reflecting challenges in recognition and treatment. Talquetamab, a bispecific CD3 T-cell engager targeting G-protein coupled receptor family C group 5 member D (GPRC5D), has emerged as a promising immunotherapy for relapsed/refractory MM (RRMM). In August 2023, talquetamab received accelerated approval from the US FDA for RRMM treatment, followed by conditional marketing authorization from the EMA. Clinical trials demonstrated talquetamab's efficacy, with overall response rates (ORR) of 69% and 76% in heavily pretreated RRMM patients. The phase I monumenTAL-1 trial showcased talquetamab's effectiveness, particularly in high-risk MM and extramedullary disease, with ORRs around 71-74%. Subsequent phase 2 results reaffirmed its efficacy, even in patients with prior T-cell redirection therapies. Combination therapy with daratumumab further enhanced talquetamab's efficacy, addressing concerns of T cell exhaustion. Pharmacokinetic studies revealed sustained responses and manageable adverse events with subcutaneous administration, facilitating convenient dosing regimens. However, talquetamab carries risks of cytokine release syndrome (CRS) and neurologic toxicity, necessitating close monitoring and prompt management. Common adverse events included fever, CRS, musculoskeletal pain, and infections, although severe events were infrequent. Vigilant management strategies, including prophylactic measures and supportive care, mitigate these risks. In conclusion, talquetamab represents a significant advancement in RRMM treatment, offering a promising avenue for T-cell redirection therapy. Ongoing research aims to optimize treatment sequencing and combination strategies, fostering improved outcomes for MM patients. Continued investigation will refine the strategic integration of talquetamab and other immunotherapies, paving the way for enhanced treatment efficacy and patient care in RRMM.

Loss of GABARAP mediates resistance to immunogenic chemotherapy in multiple myeloma

AbstractImmunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant antitumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and creates durable therapeutic responses in patients. However, eventual relapse and resistance to bortezomib appear inevitable. Here, by integrating patient transcriptomic data with an analysis of calreticulin (CRT) protein interactors, we found that GABA type A receptor–associated protein (GABARAP) is a key player whose loss prevented tumor cell death from being perceived as immunogenic after bortezomib treatment. GABARAP is located on chromosome 17p, which is commonly deleted in patients with high risk MM. GABARAP deletion impaired the exposure of the eat-me signal CRT on the surface of dying MM cells in vitro and in vivo, thus reducing tumor cell phagocytosis by dendritic cells and the subsequent antitumor T-cell response. Low GABARAP was independently associated with shorter survival in patients with MM and reduced tumor immune infiltration. Mechanistically, we found that GABARAP deletion blocked ICD signaling by decreasing autophagy and altering Golgi apparatus morphology, with consequent defects in the downstream vesicular transport of CRT. Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure, and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, such as bortezomib, with an autophagy inducer, such as rapamycin, may improve patient outcomes in MM, in which low GABARAP in the form of del(17p) is common and leads to worse outcomes.

Abstract 1223: KDM6A orchestrates NK cell response via CD38/48 regulation in multiple myeloma

Abstract Daratumumab (Dara), a first-in-class humanized monoclonal antibody targeting CD38, demonstrates notable efficacy in both newly diagnosed and relapsed/refractory multiple myeloma (MM) when administrated alone or in combination with other agents. However, the development of Dara resistance and subsequent relapse is common.To identify the tumor-intrinsic genes involved in resistance to NK-mediated cytotoxicity in the presence of Dara in MM cells, we conducted an in vitro genome-wide CRISPR-Cas9 knockout (KO) screen and found 433 genes exhibiting a positive correlation with MM cytotoxicity elicited by Dara and primary NK cells. Remarkably, 16 of these genes demonstrated a consistent correlation with cytolytic activity across the majority of the 36 cancer types in the TCGA database.The efficacy of Dara is closely linked to the expression of CD38, with nonresponders exhibiting low CD38 expression. Therefore, we conducted another CRISPR screen to identify the genes whose KO resulted in diminished CD38 expression. The genes that overlapped in these two screens are implicated in regulating both Dara-mediated ADCC and CD38 expression. Our focus turned to KDM6A among the overlapping genes. We validated that KDM6A KO significantly decreased CD38 expression and that reintroducing KDM6A into KDM6A KO cells restored the expression of CD38 and Dara-induced cytotoxicity.KDM6A demethylates lysine 27 of histone H3 (H3K27) to promote gene expression. Our ChIP-seq data unveiled that KDM6A-KO cells exhibited an increased H3K27me3 level at the CD38 promoter area than control cells. Remarkably, this pattern was consistent with Dara-resistant cell lines, which displayed reduced CD38 expression alongside elevated levels of H3K27me3 at the CD38 promoter. Interestingly, we found that CD38 overexpression only partially restored the sensitivity of KDM6A KO cells to Dara treatment, implying the existence of an additional mechanism. We performed RNA-seq in KDM6A KO cells and found CD48, an NK-activating ligand, was significantly repressed. Overexpression of CD48 in KDM6A KO cells resulted in a substantial increase in the secretion of Granzyme B and Perforin by NK cells and restored the activity of NK cells and re-sensitized KDM6A KO cells to Dara treatment. These data suggest that KDM6A mediates Dara-mediated ADCC sensitivity through the dual regulation of CD38 and CD48. KDM6A acts to oppose the EZH2/PRC2 complex by demethylating H3K27me3, and we found that Tazemetostat (Taze), an FDA-approved EZH2 inhibitor, increased the expression of CD38 and CD48, especially in KDM6A-KO cells. Importantly, Taze also restored the sensitivity of KDM6A KO cells to Dara-mediated NK cell cytotoxicity. In summary, our findings illuminate the dual role of KDM6A in enhancing the efficacy of Dara in MM. Imitating KDM6A function using an FDA-approved inhibitor holds promise in overcoming Dara resistance and improving patient outcomes in MM. Citation Format: Jiye Liu, Lijie Xing, Jiang Li, Kenneth Wen, Ning Liu, Yuntong Liu, Annamaria Gulla, Nikhil Munshi, Teru Hideshima, Kenneth Carl Anderson. KDM6A orchestrates NK cell response via CD38/48 regulation in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1223.

Risk factors of early disease progression and decreased survival for multiple myeloma patients after upfront autologous stem cell transplantation.

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post-ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08-3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53-4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31-0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32-0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05-4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03-7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45-34.59), post-ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09-28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23-6.17) experienced shorter OS. In contrast, post-ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17-0.79) and post-ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24-0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post-ASCT outcome prediction beyond clinical trials.

MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis

BackgroundProteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failure. Therefore, the mechanisms underlying PI resistance in MM require further investigation.MethodsWe used several MM cell lines to establish PI-resistant MM cell lines. We performed RNA microarray and EccDNA-seq in MM cell lines and collected human primary MM samples to explore gene profiles. We evaluated the effect of MUC20 on cuproptosis of PI-resistant MM cells using Co-immunoprecipitation (Co-IP), Seahorse bioenergetic profiling and in vivo assay.ResultsThis study revealed that the downregulation of Mucin 20 (MUC20) could predict PI sensitivity and outcomes in MM patients. Besides, MUC20 attenuated PI resistance in MM cells by inducing cuproptosis via the inhibition of cyclin-dependent kinase inhibitor 2 A expression (CDKN2A), which was achieved by hindering MET proto-oncogene, receptor tyrosine kinase (MET) activation. Moreover, MUC20 suppressed MET activation by repressing insulin-like growth factor receptor-1 (IGF-1R) lactylation in PI-resistant MM cells. This study is the first to perform extrachromosomal circular DNA (eccDNA) sequencing for MM, and it revealed that eccDNA induced PI resistance by amplifying kinesin family member 3 C (KIF3C) to reduce MUC20 expression in MM.ConclusionOur findings indicated that MUC20 regulated by eccDNA alleviates PI resistance of MM by modulating cuproptosis, which would provide novel strategies for the treatment of PI-resistant MM.

Abstract P24: GABARAP deficiency drives resistance to immunogenic chemotherapy in multiple myeloma

Abstract P24: GABARAP deficiency drives resistance to immunogenic chemotherapy in multiple myeloma

Treatment Pattern, Healthcare Resource Utilization and Symptom Burden Among Patients with Triple Class Exposed Multiple Myeloma: A Population-Based Cohort Study

PurposeThis study aims to describe the treatment patterns, outcomes, health care utilization and symptom burden of triple class exposed (TCE) relapsed/refractory patents with multiple myeloma (MM) receiving a subsequent line of treatment (LOT). MethodsThis is a retrospective observational cohort study using administrative databases in Ontario, Canada. Outcomes were captured for TCE patients receiving a subsequent LOT and included: treatment regimen details, time to next treatment (TTNT), overall survival (OS), health care utilization, palliative care referral, and patient reported symptoms. ResultsOf the 16,777 patients diagnosed with MM between 2007-2021 in Ontario, 1358 (8%) patients were classified as TCE. Among the TCE MM patients, 489 (36%) received a subsequent LOT. The two most commonly administered therapies post TCE were carfilzomib/dexamethasone (n = 111, 22%) and pomalidomide/dexamethasone(n = 95, 19%). Median TTNT was 1.7 months (95%CI 1.2-2.4 months) and median OS 12.8 months (95%CI 10.8-16.5). Healthcare utilization was high with 276 (56%) of patients evaluated in an emergency department (ED) or admitted to hospital. There was high symptom burden as reported by patients with moderate-severe impairment in well-being, fatigue, pain and drowsiness noted in greater than 25% of the cohort. Palliative care referrals rates were low with only 10% (n = 48) patients referred to palliative care. Among the patients that died during study follow up, the majority died in hospital (n = 147,44%). ConclusionOur study reports one of the largest series of real-world TCE patients published and demonstrates the poor outcomes of TCE patients receiving a subsequent LOT.

Renal outcome in multiple myeloma patients with cast nephropathy: a retrospective analysis of potential predictive values on clinical and renal outcome

ABSTRACT Objective Cast nephropathy (CN) is the leading cause of acute kidney injury (AKI) in multiple myeloma (MM). Since it is sparsely documented why some patients with CN do achieve a renal response while others do not, we describe a single-center cohort of patients with multiple myeloma and biopsy-confirmed CN to evaluate potential markers of renal response. Methods The data was collected as a retrospective, single-center analysis of CN-patients treated at the Medical University Vienna between 01/01/2004 and 01/01/2022. Baseline parameters and clinical outcome was compared between renal responders and non-responders. Results Among 28 patients with CN, n = 23 were assessed for renal response (14 responders; 9 non-responders). Renal responders were younger (median age: 61 years; 77 years, p = 0.039), showed higher overall survival (153months; 58months, p = 0.044) and achieved hematologic response (≥PR) to first-line therapy (p = 0.029), and complete hematologic response (CR) at any time (p = 0.025) significantly more often. Further, we could show that rapid initiation of anti-myeloma therapy after initial presentation correlated significantly with renal response (median 9 days; 27 days, p = 0.016). Analyses of kidney biopsy specimens revealed that patients with a high IF/TA score showed end stage renal disease (dialysis ≥ 3 months) significantly more often (p = <0.001). Discussion In summary, our data suggests, that a rapid start with systemic hematologic treatment in patients with MM and CN is crucial and achieving an early hematologic response is important for renal recovery. Moreover, achieving a deep hematologic response and subsequent renal recovery improves clinical outcome as reflected by an overall survival benefit.

Outcomes in Multiple Myeloma Patients Progressing after BCMA-Directed Chimeric Antigen Receptor T Cell (CART) Therapy

Outcomes in Multiple Myeloma Patients Progressing after BCMA-Directed Chimeric Antigen Receptor T Cell (CART) Therapy

Racial Difference in Survival Outcomes of Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant. 2010 to 2020 NCDB Database Analysis

Racial Difference in Survival Outcomes of Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant. 2010 to 2020 NCDB Database Analysis

Outcome of Multiple Myeloma Patients Undergoing Allogeneic Stem Cell Transplant with Post-Transplant Cyclophosphamide – a Single Center Experience

Outcome of Multiple Myeloma Patients Undergoing Allogeneic Stem Cell Transplant with Post-Transplant Cyclophosphamide – a Single Center Experience

Risk factors for the outcome and prognosis of multiple myeloma patients with pathological fractures undergoing percutaneous vertebroplasty.

This study focuses on the clinical features affecting the outcome and prognosis of multiple myeloma (MM) associated with spinal fractures. We retrospectively analyzed the clinical data of 194 MM patients with pathologic thoracic or lumbar spine fractures admitted to Dongying People's Hospital from April 2005 to February 2021. Patients were categorized into effective and ineffective groups based on post-treatment pain scores and mobility to analyze the influencing factors on the efficacy. Univariate analysis showed that age ≥60 years, number of vertebral fractures ≥2, and conservative treatment were associated with the outcomes. The number of vertebral fractures ≥2 (OR=2.198, P=0.034) and conservative treatment (OR=1.685, P=0.012) were identified as independent risk factors. In addition, survival curves were depicted using the Kaplan-Meier method, and independent risk factors affecting 2-year survival included efficacy (HR=17.924, P<0.001), age (HR=3.544, P=0.003) and International Staging System staging (HR=10.770, P=0.001). Finally, we constructed a high-accuracy prognostic model for predicting 2-year survival of MM patients with pathologic fractures (AUC=0.756). In conclusion, this study identified independent risk factors affecting the outcome and survival of MM patients with morbid fractures by systematically analyzing clinical characteristics and constructing a survival prediction model, thus providing effective guideline for clinical treatment.

Impact of Visceral Obesity on Clinical Outcome and Quality of Life for Patients with Multiple Myeloma: A Secondary Data Analysis of STaMINA (BMT CTN 0702) Trial

Obesity is a common health problem among multiple myeloma (MM) patients, and it has been linked to poor clinical outcomes and quality of life (QOL). We conducted a secondary analysis of the BMT CTN 0702, a randomized, controlled trial comparing outcomes of three treatment interventions after a single hematopoietic cell transplant (HCT) (N = 758), to investigate the impact of visceral obesity, as measured by waist-to-hip ratio (WHR), on clinical outcomes and QOL in MM patients. A total of 549 MM patients, median age 55.5 years, were enrolled in the study. The majority of patients received triple-drug antimyeloma initial therapy before enrollment, and 29% had high- risk disease according to cytogenetic assessment. The median follow-up time was 6 years. There was no significant association between WHR and progression-free survival (PFS) or overall survival (OS) in MM patients undergoing HCT. Similarly, body mass index (BMI) did not significantly predict PFS or OS. Furthermore, there was no significant correlation between WHR and QOL measures. In conclusion, this study suggests that visceral obesity, as measured by WHR, may not have a significant impact on clinical outcomes in MM patients undergoing HCT. These findings add to the existing literature on the topic and provide valuable information for healthcare professionals and MM patients. Further studies are needed to confirm these results and to investigate other potential factors that may affect clinical outcomes and QOL in this patient population using modern imaging technologies to assess visceral obesity.

Predictors of early morbidity and mortality in newly diagnosed multiple myeloma: data from five randomized, controlled, phase III trials in 3700 patients

Early morbidity and mortality affect patient outcomes in multiple myeloma. Thus, we dissected the incidence and causes of morbidity/mortality during induction therapy (IT) for newly diagnosed multiple myeloma (NDMM), and developed/validated a predictive risk score. We evaluated 3700 transplant-eligible NDMM patients treated in 2005–2020 with novel agent-based triplet/quadruplet IT. Primary endpoints were severe infections, death, or a combination of both. Patients were divided in a training (n = 1333) and three validation cohorts (n = 2367). During IT, 11.8%, 1.8%, and 12.5% of patients in the training cohort experienced severe infections, death, or both, respectively. Four major, baseline risk factors for severe infection/death were identified: low platelet count (<150/nL), ISS III, higher WHO performance status (>1), and age (>60 years). A risk score (1 risk factor=1 point) stratified patients in low (39.5%; 0 points), intermediate (41.9%; 1 point), and high (18.6%; ≥2 points) risk. The risk for severe infection/death increased from 7.7% vs. 11.5% vs. 23.3% in the low- vs. intermediate- vs. high-risk groups (p < 0.001). The risk score was independently validated in three trials incorporating quadruplet IT with an anti-CD38 antibody. Our analyses established a robust and easy-to-use score to identify NDMM patients at risk of severe infection/death, covering the latest quadruplet induction therapies. Trial registrations: HOVON-65/GMMG-HD4: EudraCT No. 2004-000944-26. GMMG-MM5: EudraCT No. 2010-019173-16. GMMG-HD6: NCT02495922. EMN02/HOVON-95: NCT01208766. GMMG-HD7: NCT03617731.

Abstract B020: Genetic markers, first-line treatment, and survival among Hispanic patients with multiple myeloma: A population-based study in Puerto Rico

Abstract Background: Research on the genetic markers, treatment, and survival of multiple myeloma (MM) among Hispanics is limited. Most population-based registries do not comprehensively collect cancer-related biological and genetic markers, which limits the use of these registries to address critical research questions. We used the Puerto Rico Central Cancer Registry (PRCCR) and the PRCCR-Health Insurance Linkage Database (PRCCR-HILD) to evaluate these factors among patients diagnosed with MM in Puerto Rico (PR). Methods: A retrospective cohort study was conducted among MM patients in PR between 2015 and 2019. We developed a robust sub-database that expands the quality and quantity of data regularly collected by the PRCCR and health insurance claims by integrating data from PRCCR’s cancer database, Electronic Medical Records, Pathology Reports database, and PRCCR-HILD. Descriptive statistics were used to present an epidemiological profile of the study group. Bivariate analyses were performed to evaluate associations between treatment patterns and patient characteristics. Multivariable Cox regression models were used to estimate the magnitude of the association between overall mortality among patients with MM and different characteristics. Results: The study cohort consisted of 716 patients; 49.6% were male, the median age at diagnosis was 69 years, and 76.7% had a comorbidity index score ³2. High-risk chromosomal abnormalities (HRCAs), which include at least one of t(4;14), t(14;16), Del(17p), and t(14;20), were found in 23.2% of patients. Around 88% of MM patients had documented evidence of treatment, and nearly half of all patients began treatment after 30 days (49.1%) of diagnosis. The most common treatment was bortezomib-based triplet (29.1%), followed by bortezomib-based doublet (25.9%). Based on the multivariable Cox models, the risk of dying was greater among patients who had chromosome 1 abnormalities (C1As) (HRAdjusted: 1.28, 95% CI: 0.99-1.66) or HRCAs (HRAdjusted: 1.39, 95% CI: 1.04-1.86) than patients without C1As or HRCAs, respectively. Furthermore, the risk of dying was lower among those receiving treatment after controlling by potential confounders (HRAdjusted: 0.44, 95% CI: 0.32-0.61). Among those receiving treatment, the bortezomib triplet showed better results than dexamethasone (HRAdjusted: 2.62, 95% CI: 1.63-4.20) and bortezomib-based doublet (HRAdjusted: 1.72, 95% CI: 1.14-2.60). Conclusion: This study provides the first description of the prevalence of genetic markers in patients with MM in PR, integrating epidemiological, clinical, and health claims data. Our analysis confirms that HRCAs and C1As remain as important predictor factors in determining the outcomes of MM patients. In addition, treatment patterns in PR Hispanic population suggest a longer median time to treatment initiation than other US studies, which warrants follow-up. These findings highlight the importance of establishing a broader understanding of the genetic and treatment-related factors associated with MM outcomes in different racial/ethnic groups. Citation Format: Tonatiuh Suárez Ramos, Maira A. Castañeda-Avila, Carlos R. Torres-Cintrón, Axel Gierbolini-Bermúdez, Guillermo Tortolero-Luna, Karen J. Ortiz-Ortiz. Genetic markers, first-line treatment, and survival among Hispanic patients with multiple myeloma: A population-based study in Puerto Rico [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B020.

A Tumor-Bearing Murine Xenograft Model As a Bioassay for Assessing CAR-T Product Potency Shows Positive Predictive Value for Clinical Performance

Potency assays are required for cellular and gene therapy (CGT) final product (FP) lot release, stability testing, and manufacturing updates, as per the FDA draft guidance on Potency Tests for CGT Products (2011), and Manufacturing Changes and Comparability for Human CGT Products (2023). These assays by definition measure the ability of a product to effect a desired result, and the FDA allows for “considerable flexibility” in determining the appropriate potency assay. However, standard in vitro potency assays are limited in their capacity to meaningfully assess manufacturing comparability and consistency, or product quality to provide predictive value for clinical performance. For chimeric antigen receptor (CAR)-T cell products, certificates of analysis typically report key FP attributes such as CAR expression, cell concentration and viability, impurities and target-specific in vitro potency, among others. However, clinical effectiveness of CAR-T is dependent on complex pharmacokinetics (PK)/ pharmacodynamics (PD) including in vivo engraftment, trafficking, drug exposure kinetics, tumor antigen-driven T cell expansion in tumor microenvironment, survival and persistence, and other factors that are not easily recapitulated in short-term in vitro assays. We developed a bioassay for assessing CAR-T FP potency using a tumor-bearing murine NSG xenograft model to evaluate in vivo performance of GMP-manufactured autologous (Auto) or allogeneic (Allo) CAR-T FPs. We hypothesized that this complex in vivo system may better model PK/PD and provide a more meaningful way to assess CAR-T FP potency. Preclinical dose-finding data from both RUO and GMP anti-BCMA CAR-T lots were used to establish a potency specification for RPMI-8226 tumor control at a “stress dose” of 5e6 CAR-T cells at &amp;lt;60% of the tumor volume compared to the untreated control group at 21 days after CAR-T cell infusion. Using these specifications, we evaluated the in vivo potency performance of GMP-manufactured Auto FP samples (P-BCMA-101; NCT03288493) generated from multiple myeloma (MM) patients and administered in the clinic with known responses ranging from poor (no response or stable disease) to significant (very good partial response [VGPR] or stringent complete response [sCR]). In addition, GMP-manufactured Allo FP samples generated from healthy donors (P-BMCA-ALLO1; NCT04960579) were also tested. We report that half of the P-BCMA-101 products (50%) previously demonstrating favorable clinical outcomes in MM patients were also able to control RPMI-8226 tumor in vivo, while none of the P-BCMA-101 products (0%) that resulted in poor clinical responses were capable of tumor control. These data show translational relevance considering the known clinical outcomes in MM patients, albeit at a high level of stringency at current specifications. Interestingly, all the Allo products (100%) performed at least as well as or better than the Auto products capable of controlling tumor, demonstrating a greater potency of Allo CAR-T cells manufactured from healthy donors. There is great demand for potency assays that can reliably assess manufacturing consistency and product quality, and that might provide some level of predictive value for clinical performance, especially considering the current limitations of standard in vitro potency assays. In vivo potency bioassays have been proposed or utilized for other products with complex biological mechanisms of action including vaccines, gene therapies, and other cell therapy products. The potency bioassay described herein demonstrated a level of positive predictive value for clinical performance using Auto FPs of known clinical outcome in MM patients. In the Auto CAR-T setting, this assay could be utilized for correlative studies including possible biomarker identification. In the Allo CAR-T setting, this potency bioassay may inform FP manufacturing consistency and quality for lot release to ensure patients receive only the highest quality products.

Second Line Treatment and Outcomes of Patients with Multiple Myeloma: A Real World Multi-Institutional Report from the Canadian Myeloma Research Group (CMRG) Database

Introduction: The treatment of multiple myeloma (MM) has evolved rapidly, with various combinations of immunomodulators (IMiDs), proteasome inhibitors (PIs), corticosteroids and autologous stem cell transplantation (ASCT) utilized in newly diagnosed (ND) patients; in some jurisdictions, monoclonal antibodies (MABs) are also incorporated in first-line treatment. Over the last decade, the standard of care in Canada for NDMM in fit younger patients has consistently been induction (CyBorD/more recently RVD) followed by ASCT and maintenance lenalidomide (len) until progression. In transplant-ineligible patients, bortezomib- or len-based treatments in doublets or triplets have been used frontline. At relapse, options have included re-induction followed by 2nd ASCT or doublet/triplet combinations until progression. Limited comparative data are available to support any one approach. The aim of this retrospective study was to assess the treatment patterns and outcomes of MM patients treated at 1st relapse in a real-world setting. This data may be useful to myeloma stakeholders when evaluating the potential impact of even newer novel immunotherapeutic agents in patients in who have had 1 prior line of treatment. Methods: We performed a retrospective observational study using the Canadian Myeloma Research Group Database (CMRG-DB), which is a prospectively maintained disease-specific database with ≥ 9000 patients enrolled from 16 academic sites across Canada. All MM patients who initiated second-line therapy between 01/12/2010 - 30/06/2022 were included and results were analyzed up to 23/05/2023. We aimed to evaluate the following outcomes for each second-line regimen: overall response rate (ORR), progression-free survival (PFS) and overall survival (OS), calculated from the start of second-line therapy. Survival was estimated using Kaplan-Meier methods and compared between groups using the log rank test. Results: A total of 3569 patients were identified: 1638 (45.9%) who had prior ASCT and 1931 (54.1%) non-ASCT patients. 2715 (76%) patients were bortezomib-exposed in first line, 1052 (30%) were lenalidomide-exposed; 22% had high-risk cytogenetics. The most commonly used second-line regimens were Rd in 1325 (37%) of patients, DRd in 346 (10%), CyBorD in 291 (8%), 2nd ASCT in 270 (8%), RVd in 201 (6%) and DVd in 167 (5%). Outcomes including ORR, ≥ VGPR rate, PFS and OS from second-line treatment for regimens with &amp;gt;50 patients are presented in Table 1. Among all patients, the highest ORRs were seen with DRd (90%), 2nd ASCT (89%), Kd/KCd (79%), RVd (78.1%) and KRd (74%); DRd had the highest ≥ VGPR rate (66%). In patients who had received bortezomib-based first line treatment, the second line ORRs were 96%, 98% and 95% for VRd, KRd and DRd, respectively, with a corresponding median PFS of 20 months (VRd), 19 months (KRd) and 28 months (DRd). For patients who had len-based first line treatment, the second line ORRs were 80% for Kd/KCd and 95% for DVd with a median PFS of 16 months (Kd/KCd) and 11 months (DVd), respectively. The median PFS was 41 months after 2 nd ASCT; of these patients, 68% were exposed to bortezomib in first line and 34% were len exposed in first line. The median PFS was 30 months in those who had len maintenance after their 1 st transplant compared to 60 months in those with no initial maintenance. Conclusion: In this real-world observational study we demonstrate that Canadian patients achieved results comparable those noted in prospective clinical trials leading to the approval of these agents in the second-line setting. Triplet combinations with an IMID backbone, including DRd, KRd and Ixa-Rd, had high response rates, with DRd offering the longest PFS. Patients undergoing 2 nd ASCT had ORRs and PFS comparable to DRd, although these results were likely influenced by selection of a population with a favorable response to 1st ASCT . Given the expanding use of IMID, PI and MAB combinations in first-line, our results highlight the need for better modalities at the time of 1 st relapse. Earlier integration of “novel” agents, including CAR-T therapy, bi-specifics, conjugated antibodies and CEL-MoDs-even in the second-line setting–is likely required to improve on these outcomes. The current analysis provides efficacy benchmarks to guide their implementation. Financial Support: CMRG received financial support from Janssen Inc. for the conduct of this study

A 5-Stage System for ASCT Multiple Myeloma

652. Multiple Myeloma: Clinical and Epidemiological INTRODUCTION: In the last three decades, significant advancements in multiple myeloma (MM) treatment, including immunomodulators, targeted therapies, chemotherapy combinations, autologous stem cell transplantation (ASCT), and CAR-T therapy, have emerged. ASCT offers hope for MM patients by using high-dose chemotherapy with stem cell support. However, it carries risks of severe toxicity. Despite evaluating factors like age, performance status, and co-morbidities for ASCT eligibility, outcomes for MM patients still vary greatly. Various models, such as the ISS-series systems, have been developed to assess risk factors for progression-free and overall survival We conducted a study on 5,259 ASCT patients since 1989, identifying 7 easy variables (ISS stage, diagnosis-transplant interval, ferritin, transferrin, LDH, age, and gender) and creating a 5-stage system. This system helps evaluate the risk of MM patients before ASCT. METHODS: In this retrospective study, data from 5,259 MM patients receiving ASCT (1989-2022) were collected (median follow-up: 57 months). We assessed 30 clinical variables pre-ASCT. Multiple imputation was used to deal with the missing values. Patients were split into a 70% training set and a 30% validation set. Univariate/multivariate Cox regression analysis identified 7 clinical and demographic signatures. Signatures were scored based on hazard ratios normalized to ISS III vs. ISS I&amp;II. K-adaptive partitioning generated a 5-stage system, ATM5S, evenly distributed and validated in the training set. Harrel's c-index was used to compare ATM5S with the current myeloma systems. RESULTS: 3683 patients (70%) in the test cohort had a median age of 59.6, median PFS 38.8 month and median OS 56.1 month. IgG was the most common isotype (55%). Univariate Cox analysis showed that 27 variables were significant predictors for both PFS and OS. Multivariate Cox analysis showed that time from diagnosis to transplant, ferritin, transferrin, LDH, ISS stage, lymphocytes, platelets, calcium, gender and age were independent prognostic factors for both OS and PFS. We selected the most easy, understandable and well-distributed (with high-risk group&amp;gt;20%) 7 variables: ISS, time from diagnosis to transplant, ferritin, transferrin, LDH, age and gender and developed a score system, which resulted into a 5-stage system (ATM5S) by k-adaptive partitioning. This staging system also demonstrated a significant discriminatory effect in the validation set (30%, 1576 patients). CONCLUSIONS: The Arkansas Transplant-Myeloma 5-Stage System (ATM5S) showed a promising performance in both training and validation cohorts.

Treatment Patterns and Outcomes in Patients with Multiple Myeloma Who Received Ixazomib and in Patients with Triple-Class Refractory Multiple Myeloma: A Retrospective, Observational, Real-World Historical Database Analysis Study from China

Background: Multiple myeloma (MM) is a fatal, malignant disease of plasma cells characterized by an abnormal proliferation of monoclonal antibodies. China is estimated to have 22,450 newly diagnosed (ND) cases of MM and 17,360 related deaths in 2022. Emerging novel therapies have significantly improved survival in MM, and treatment guidelines have been updated to reflect these advances. Ninlaro® (ixazomib) is the first oral proteasome inhibitor (PI) approved by the US FDA in 2015 and by China's National Medical Products Administration in 2018 (conditionally) for MM patients receiving ≥1 prior therapy owing to its convincing efficacy and well-tolerated safety profile as seen in the landmark Phase III TOURMALINE-MM1 trial and the China Continuation Study. Novel drugs such as PIs, immunomodulatory drugs (IMDs), and anti-CD-38 monoclonal antibodies are the core component of MM treatment and have improved patient outcomes considerably. However, many patients remain refractory to these drugs (triple-class refractory, TCR) and have poor clinical outcomes. There is a lack of real-world evidence characterizing treatment patterns and outcomes of MM patients receiving ixazomib and TCR-MM patients, in China. The objective of this study is to bridge this data gap by providing vital information on the treatment patterns and outcomes, and healthcare resource utilization in Chinese MM patients receiving ixazomib and TCR-MM patients in real-world clinical practice. Study Design and Methods: This study is an ongoing, single-centre, non-interventional, retrospective database analysis study of MM patients identified from the Chinese National Longitudinal Cohort of Haematologic Diseases (NICHE)-MM registry, a historical and ongoing longitudinal data registry of the Institute of Haematology and Blood Diseases Hospital (IHBDH), and representing the top-tier MM care in China. The patients will be divided into two groups. Patients (aged ≥18 years) with a confirmed MM diagnosis receiving all ixazomib-based regimen as 2nd-line and above therapy (RR-MM), or as a 1st-line therapy (ND-MM) will form group one and TCR-MM patients' refractory to at least one IMiD (lenalidomide, pomalidomide or thalidomide), one PI (bortezomib, ixazomib, or carfilzomib) and one anti-CD-38 monoclonal antibody (daratumumab and isatuximab) will form group two. TCR-MM patients receiving ixazomib will be part of both groups. Patients enrolled in clinical trials will be excluded. The data for analysis will be collected from the ixazomib launch date in China (April 12, 2018) and/or the index date of the first patient enrolled in ixazomib Named Patient Program to September 2023 (tentative). Since 2000 till January 2023, the NICHE-MM registry has enrolled 3,329 MM patients of whom 156 patients have received ixazomib. This is the preliminary sample count and the final sample size will be calculated during data cleaning and analysis phases. The primary objective of this study will be to determine 1) treatment patterns and responses by lines of treatments and 2) time-to-event outcomes. The treatment patterns will include treatment name, dosage, type (induction, consolidation, or maintenance), number of cycles, duration and severe adverse event causing hospitalization. The treatment responses will include complete response (CR), stringent CR, partial response (PR), very good PR, minimal response, stable disease, and progressive disease as defined by the International Myeloma Working Group. The overall response rate of the last line of treatment for both study groups will be calculated as composite endpoint. Time-to-event outcomes will include progression-free survival, overall survival, duration of therapy, and time to next line of treatment in ND/RR-MM and TCR-MM patient groups. Secondary objectives will include assessment of patients' demographic, disease and clinical characteristics. Depending on data availability, the exploratory objective will be to determine the healthcare resource utilization and costs incurred by patients in both groups. Subgroup analysis between ND-MM vs. RR-MM or RR-MM patients receiving ixazomib in 2nd-line setting vs. TCR-MM patients receiving ixazomib in &amp;gt;3rd-line setting is also planned. Descriptive statistics will be used for the analyses. Our findings will also help clinicians in making strategic decision about more apt positioning of ixazomib in the treatment algorithm of MM.