Functional High Risk Research Articles

Ciltacabtagene autoleucel vs standard of care in patients with functional high-risk multiple myeloma: CARTITUDE-4 subgroup analysis.

7504 Background: Functional high-risk (FHR) multiple myeloma (MM) is associated with poor prognosis. In CARTITUDE-4, a single ciltacabtagene autoleucel (cilta-cel) infusion significantly improved progression-free survival (PFS) vs established standard of care (SC; hazard ratio [HR], 0.26 [95% CI, 0.18–0.38]; P<.0001) in patients (pts) with lenalidomide (len)-refractory MM after 1–3 prior lines of treatment (tx; LOT). This post hoc subgroup analysis of CARTITUDE-4 reports outcomes for pts who received cilta-cel vs SC as second-line tx, including pts with FHR MM. Methods: Pts randomized to cilta-cel underwent apheresis, received PVd or DPd bridging tx, and then cilta-cel infusion (target dose, 0.75×106 CAR+ viable T cells/kg) 5–7 d after the start of lymphodepletion. Pts randomized to SC received PVd or DPd until progressive disease (PD). FHR was defined as PD within 18 mo after receiving autologous SCT or the start of initial frontline tx. Efficacy was assessed in randomized pts (intent to treat) and safety in pts who received any part of study tx. Results: 136 pts received cilta-cel (n=68) or SC (n=68) as second-line tx. Of these, 79 had FHR MM (cilta-cel, n=40; SC, n=39). Median PFS was longer among pts who received cilta-cel vs SC as second-line tx including the subset who had FHR MM (Table). Overall survival was immature at the time of this analysis. A greater proportion of pts who received cilta-cel vs SC as second-line tx had an overall response, complete response (CR) or better, minimal residual disease (MRD) negativity, and longer median duration of response (DOR), with similar observations among the FHR subset. Proportion of pts with grade ≥3 TEAEs who received cilta-cel vs SC as second-line tx was comparable (96% vs 96%) including the subset with FHR MM (100% vs 97%). Among pts who received second-line tx, 22 died (cilta-cel, n=11; SC, n=11), 16 of whom had FHR MM (n=7; n=9). Conclusions: In pts with len-refractory FHR MM after 1 prior LOT, cilta-cel improved outcomes vs SC and had a safety profile consistent with the known mechanism of action of CAR-T tx, suggesting cilta-cel may overcome the poor prognosis associated with FHR MM. Clinical trial information: NCT04181827 . [Table: see text]

Serum indicators in functional high-risk multiple myeloma patients undertaking proteasome inhibitors therapy: a retrospective study

ABSTRACT Objectives Multiple myeloma (MM) is a class of malignant plasma cell diseases. An increasing application of autologous stem cell transplantation (ASCT) and anti-myeloma agents represented by proteasome inhibitors (PIs) has improved the response rates and survival of MM patients. Patients progressing within 12 months were recently categorized with functional high-risk (FHR), which could not be clarified by existing genetic risk factors, with poor outcomes. Our study aimed to investigate clinical indices related to FHR and seek prognostic roles in transplant-eligible MM patients. Methods Demographic and individual baseline clinical characteristics were compared by using the Pearson's chi-square and Mann-Whitney U test. Progression-free survival (PFS) and overall survival (OS) were described by Kaplan-Meier estimates and compared using the log-rank test. Logistic regression analysis was used to assess the association of baseline characteristics at MM diagnosis with FHR status. Results From 18th January 2010 to 1st December 2022, 216 patients were included and divided into two groups according to the FHR status. There was no difference in baseline data between the two groups. Renal impairment (RI, Scr > 2 mg/dL) was common in MM patients and made sense in FHR status. AST levels were validated as independent predictors for FHR status (p = 0.019). Discussion Patients with RI or higher AST levels (AST > 40 U/L) tended to have worse outcomes. However, transplants had apparently improved prognoses. Conclusion Therefore, in the PIs era, transplantations are still effective therapies for transplant-eligible MM patients.

Efficacy of Autologous Stem Cell Transplantation for Myeloma Patients with Suboptimal Response: A Multicenter Retrospective Analysis

Autologous stem cell transplantation (ASCT) is the standard of care for myeloma patients when partial response (PR) or better is achieved after induction therapy. However, its clinical significance in patients with suboptimal response (SR), including stable disease (SD) and progressive disease (PD) before ASCT, has not been established. Additionally, functional high-risk (FHR), including RS and early PD within 12 months, was a poor prognostic factor up to now. This study aimed to evaluate the efficacy of ASCT in myeloma patients having SR in novel agent era. This multicenter, retrospective study was conducted using the Transplant Registry Unified Management Program (TRUMP) database of the Japanese Society of Transplantation and Cellular Therapy (JSTCT) and included 3898 patients with transplant-eligible patients with newly diagnosed multiple myeloma who underwent ASCT between 2007 and 2020 and were followed up until 2021. The SR rate was 4.7% including 1.7% of PD. In survival time analysis for overall cases, The significant difference of PFS between the VGPR and PR groups were observed while there was no significant difference of OS between the VGPR and PR groups. Additionally, there was no significant difference of OS and PFS between the PR and SD groups. Therefore, we focused on the PR, SD, and PD groups as the purpose of this retrospective study was to investigate the clinical significance of ASCT in patients with SR compared with those with PR. The median age of the patients was 60 years (range, 30-77 years). In total, 1605 (97.4%), 561 (38.2%), and 512 (34.9%) patients received bortezomib, immunomodulatory drug (IMiD), and both bortezomib and IMiD, respectively. A total of 558 (38.0%) patients received reinduction therapy. There were 229 (37.7 %) patients with high-risk cytogenetic risk (HRCA). In a median follow-up period of 31.7 months, a significant difference was observed in 30-month overall survival (OS) rates between the PR, SD, and PD groups (86.3%, 78.5%, and 39.4%, respectively; p <0.001). In a comparison between the PR and SD groups, the OS in the SD group was significantly shorter than that in the PR among the patients with HRCA (p <0.001) and in the patients treated with reinduction therapy (p = 0.013). Concerning the PD group, the 30-month OS and PFS rates in the PD group were 39.4% and 17.9%. Finally, early PD within 12 months after ASCT predicted short OS, whereas OS without early PD even in the PD group was similar to that in the SD and PR groups. In conclusion, the OS in the SR was not always short, but the SR in the HRCA and the reinduction therapy groups predicted to short OS so that alternative therapeutic options to ASCT are needed. OS in the PD group was significantly short, but ASCT improved clinical outcome when early PD was not occurred even in the PD group.

EARLY RELAPSE WITHIN 18 MONTHS (ER18) IS A POWERFUL DYNAMIC PREDICTOR FOR PROGNOSIS AND COULD REVISE STATIC RISK DISTRIBUTION IN PATIENTS WITH NEWLY‐DIAGNOSED MULTIPLE MYELOMA

The duration of response to treatment is a major prognostic factor and early relapse (ER) strongly predicts inferior survival in multiple myeloma (MM) patients. But the definitions of ER in MM varied from study to study. In this study, we aimed to identify the best ER timepoint which we integrated with initial traditional risk features to formulate a novel prognostic classification incorporating both static and dynamic risk. The study was based on the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199) and a total of 629 patients diagnosed with NDMM were included in this study. We first summarized all studies about ER published to date and found that relapse within 18 months from the initial treatment or within 12 months from SCT was mostly used to define early PD in many studies. Our findings indicate that ER18 could effectively balance the bias of ER definitions for patients with or without ASCT, as well as fulfill all requirements for a dynamic risk predictor. The ER18 population (114/587; 19.4%) presented with more aggressive biologic features compared to a reference cohort (P < 0.001), with a significant short median overall survival (OS) of 28.9 months. We also described the specific transitions from static risk profile to dynamic risk distribution in our cohort and then constructed a mixed-risk pattern to identify four novel populations with distinct survival outcomes (P < 0.001). A total of 367 (67.0%) patients presented with at least one high-risk feature: those with ISS III stage, elevated LDH, and HRCAs were classified as baseline high-risk (BHR) group; 86 (23.4%) patients experienced ER18 and further defined as mixed high-risk (MHR) population, and the remaining patients were classified as static high-risk (SHR). Within patients without BHR features, the dynamic risk event (ER18) occurred in 21(11.6%) patients, defined as functional high-risk (FHR). As expected, the MHR population had the worst outcomes with a median OS of 25.9 months (P < 0.001). Of note, FHR patients had similar survival compared to SHR patients (OS: not reached vs. 71.4 months; P = 0.235; Figure 3B), supporting the importance of dynamic risk factor (ER18) as a prognostic factor and further suggesting that lack of durable response could exert an adverse impact on prognosis similar to baseline high-risk variables. Moreover, we confirmed that ER18 refined the predictive accuracy of the Revised International Staging System stage (R-ISS). Encore Abstract - previously submitted to EHA 2023 Keywords: Diagnostic and Prognostic Biomarkers, Multiple Myeloma, Risk Models No conflicts of interests pertinent to the abstract.

Clinical and genomic characterization of Chinese patients with functional high-risk multiple myeloma: A real-world validation study.

Precise risk stratification is increasingly essential in the management of multiple myeloma (MM) as some standard-risk (SR) patients still exhibit similar poor outcomes as genetically high-risk (GHR) patients in the era of novel agents. It has recently been demonstrated that functional high-risk (FHR) patients, those with suboptimal response to first-line induction therapy or early relapse within 12 months, have identifiable molecular characteristics from the SR group in the CoMMpass dataset. However, these findings lack practical validation in the real world. MM cells purified by CD138 microbeads from newly diagnosed MM (NDMM) patients received fluorescence in situ hybridization and sequencing with a 92-gene Panel. Cytogenetic abnormalities defined GHR patients with t(4;14) or t(14;16) or complete loss of functional P53 or 1q21 gain and International Staging System (ISS) stage 3. SR group was patients who did not fulfill any criteria for GHR or FHR. There were 145 patients with NDMM, 78 in the SR group, 56 in the GHR group, and 11 in the FHR group. In the FHR group, eight patients were suboptimal responses to induction therapy, and three relapsed within 12 months. We found that male patients, patients with extra-medullary plasmacytoma (EMD), circulating clonal plasma cells (CPC) ≥0.05%, and P53 mono-allelic inactivation were significantly higher in the FHR group compared to the SR group. After a median follow-up of 21.0 months, the median progression-free survival (PFS) and overall survival (OS) were 5.0 months, 19.1 months and 36.6 months in the FHR, GHR, and SR groups, respectively. Compared to the SR group, FHR patients had a higher frequency of mutations in MKI67, ERN1, and EML4. GO analysis showed that mutations in FHR were enriched for oxidative stress, chromosomal segregation, and hypoxia tolerance. The FHR found in the SR NDMM patient group has unique clinical features, including being male, with EMD and CPC, and genetic characteristics of mutations affecting oxidative stress, chromosome segregation, and hypoxia tolerance. In contrast to previous reports, our data suggested that patients with P53 mono-allelic inactivation should be classified in the GHR group rather than the FHR group.

Genomic characterization of functional high-risk multiple myeloma patients

Multiple myeloma (MM) patients with suboptimal response to induction therapy or early relapse, classified as the functional high-risk (FHR) patients, have been shown to have poor outcomes. We evaluated newly-diagnosed MM patients in the CoMMpass dataset and divided them into three groups: genomic high-risk (GHR) group for patients with t(4;14) or t(14;16) or complete loss of functional TP53 (bi-allelic deletion of TP53 or mono-allelic deletion of 17p13 (del17p13) and TP53 mutation) or 1q21 gain and International Staging System (ISS) stage 3; FHR group for patients who had no markers of GHR group but were refractory to induction therapy or had early relapse within 12 months; and standard-risk (SR) group for patients who did not fulfill any of the criteria for GHR or FHR. FHR patients had the worst survival. FHR patients are characterized by increased mutations affecting the IL-6/JAK/STAT3 pathway, and a gene expression profile associated with aberrant mitosis and DNA damage response. This is also corroborated by the association with the mutational signature associated with abnormal DNA damage response. We have also developed a machine learning based classifier that can identify most of these patients at diagnosis.

Evaluation of Functional and Cytogenetic High-Risk Multiple Myeloma Using Real-World Data

Introduction: Multiple myeloma (MM) is a heterogeneous disease with wide variability in outcomes. The presence of cytogenetic abnormalities in MM is of critical importance for prognosis and risk stratification. However, patients who may or may not have sufficient cytogenetic abnormalities to classify as high-risk can still experience rapid disease progression despite therapy, or functional high risk (FHR) disease. These two high risk cohorts comprise vulnerable subpopulations who have a significant burden of disease, and it is critical that we understand the underlying patient characteristics and optimal treatment sequence. We sought to investigate these two high risk patient populations treated in the contemporary real-world practice setting.Methods: A total of 1719 patients were identified in the COTA real-world database as having been diagnosed with active MM on or after January 1, 2015 and classified as either FHR, cytogenetic high risk (CHR), or both. The COTA real-world database is a USA-based real-world evidence database comprised of longitudinal, Health Insurance Portability and Accountability Act (HIPAA)-compliant, data on the diagnosis, clinical management, and outcomes of patients with cancer. Of the 1719 patients, 1260 were identified to be FHR, defined as relapse <18 months from initial active MM diagnosis. A total of 459 patients were identified as CHR, among which 347 were both FHR and CHR. CHR was defined as a patient having at least one of the following abnormalities: t(4;14), t(14;16), t(14;20), del(17p), 1q gain, or hypoploid. Line of therapy was applied programmatically using an algorithm based on International Myeloma Working Group criteria and clinical guidance. The primary outcome was time to next treatment (TTNT) calculated using the Kaplain Meier method. Univariate and multivariate analyses were conducted to understand predictors of rapid disease progression among high-risk patients.Results: In our real-world population, FHR patients tended to be slightly younger, African American, and treated predominantly in the academic setting (Table 1). First-line (1L) and second-line (2L) treatment patterns by category are shown in Table 2. A lower proportion of FHR patients received 1L immunomodulators as compared to the other high-risk groups, while almost half of the CHR patients received 1L stem cell transplant (SCT). In 2L, among patients not receiving 2L SCT, a higher proportion of CHR patients received a daratumamab-based treatment as compared to FHR (23.2% vs. 12.0%, respectively). We observed a longer median (95% CI) TTNT for high-risk patients receiving 2L daratumamab-based treatment as compared to patients who did not: 8.5 months (6.4-13.0) vs. 6.0 months (5.3-6.9), p=0.07 (Figure 1). Univariate and multivariate analyses showed age at diagnosis (HR: 0.98, CI: 0.97, 0.99), normal cytogenetics (HR: 0.78, CI: 0.63, 0.97), 1L immunomodulator (HR: 0.39, CI: 0.22, 0.69), 1L proteasome inhibitor (HR: 1.4, CI: 1.1, 1.8), and 1L SCT (HR: 0.22, CI: 0.15, 0.32) as significant predictors of rapid disease progression.Conclusions: Our study provides important insights comparing high risk populations with MM treated in the real-world setting. A higher proportion of CHR patients received 1L SCT and this provided the longest 1L TTNT as compared to other treatments. In 2L, among patients not receiving 2L SCT, we observed a trend towards significantly longer TTNT provided by dara-based treatment as compared to non-dara based treatment; however, our TTNT is lower than progression-free survival results observed in pivotal trials. We identified potential underlying differences in our patient populations that may be driving the predictors of rapid disease progression, including 1L SCT eligibility and renal disease, and these will be further investigated in propensity score matched populations. Future research will continue to explore optimal treatment sequences in high-risk populations with multiple myeloma to improve patient outcomes. These data highlight an urgent need to better predict FHR patients at diagnosis and develop clinical trials incorporating novel compounds in high risk patients. [Display omitted] DisclosuresHansen: COTA, Inc.: Current Employment. Belli: COTA, Inc.: Current Employment, Other: Equity ownership. Goran: COTA, Inc.: Current Employment. Wang: COTA, Inc.: Current Employment, Other: Equity ownership.

Identifying the Genomic Profile of Functional High-Risk Multiple Myeloma Patients

Background: Multiple myeloma (MM) patients with suboptimal response to induction therapy or early relapse, classified as the functional high-risk (FHR) patients, have been shown to have poor outcomes. However, the current risk stratification at diagnosis has not been able to accurately identify these patients. In clinical practice, we saw patients who were not identified as being high-risk at diagnosis having refractory disease or early relapse. The aim of our study is to evaluate the genomic profile of FHR MM patients at diagnosis. Method: We evaluated newly-diagnosed MM patients in the CoMMpass dataset and divided them into 3 groups: genomic high-risk (GHR) group for patients with t(4;14) or t(14;16) or del17p13 and TP53 mutation or 1q gain and International Staging System (ISS) stage 3; FHR group for patients who were refractory to induction therapy or had early relapse within 12 months and without the markers of GHR group; and standard-risk (SR) group for patients who did not fulfil both criteria. We evaluated the genomic profile based on the differentially expressed genes (DEG), copy number aberrations (CNA), mutational signatures (MS), and gene set enrichment analysis (GSEA). Results: Of 512 evaluable patients, there were 345 patients in the SR group, 106 patients in the GHR group, and 61 patients in the FHR group. On the survival analysis, both FHR and GHR groups had significantly poorer outcomes as compared with the SR group, with FHR group being the worst (FHR: HR=5.19, p=3.42x10-11;GHR: HR=3.55, p=3.5x10-8) (Fig A) The DEGs in FHR and GHR groups were distinct. FHR patients were enriched for genes linked to centromeres, mitosis, DNA repair, C2H2-type zinc finger proteins, and proteasome complex. On the other hand, GHR patients were enriched for genes linked to ribosomal proteins, immunoglobulin proteins, and cell-cell junctions. As FHR patients could not be identified at diagnosis by clinical and genetic parameters, we applied established gene expression signatures of high-risk disease, including proliferation (PI), chromosomal instability (CIN70, CINSARC, CINGEC), centrosome (CI), cell death (HZDCD), and others (EMC92, HMCL7, IFM15, UAMS70, and UAMS80), to see if they could be used. Interestingly, none of these could identify all FHR patients. The best amongst these signatures was able to identify one-third of these patients. Indeed, about one-third of patients were not classified as high-risk by any of these signatures (Fig B). We next explored the use of machine learning methods on the 453 DEGs to identify a predictive model for the FHR group. Our predictive model based on random forest technique resulted in 19 significant genes with accuracy of 0.88, specificity of 0.94, sensitivity of 0.47, AUC - ROC of 0.70, F1 score of 0.48, and Matthews correlation coefficient of 0.42 (Fig C). In terms of CNA, FHR group was predominantly hyperdiploid. On the other hand, GHR group was mostly non-hyperdiploid with fewer gains of odd-numbered chromosomes, more pronounced 13q deletion, and increased 1q gain, as compared with FHR (p=1.45×10-10) and SR groups (p&amp;lt;2.2×10-16). Mutation analysis revealed that IL6-JAK-STAT3 pathway had more mutated genes per patient in FHR group, while estrogen response, KRAS, and WNT β catenin signaling pathways had more mutated genes per patient in GHR group. GHR also had higher mutational load (p=0.00331), and FGFR3 (p=1.63×10-11), PRKD2 (p=2.82×10-7), and TP53 (p=8.7×10-6) were predominantly mutated in GHR group as compared with others. MS analysis using SigProfiler with Catalogue Of Somatic Mutations in Cancer (COSMIC) reference catalogue (version 3.1) showed that as compared with SR group, FHR group had increased activity in the defective homologous recombination-based DNA damage repair signature (SBS3), while GHR group had increased activity in the AID/APOBEC family of cytidine deaminase signatures (SBS2, SBS13). Interestingly, GSEA showed enrichment in cell cycle related gene sets (G2M, E2F) in FHR group and estrogen response gene sets in GHR group (Fig D). Conclusion: Identifying FHR MM patients at diagnosis represents an unmet clinical need and in this study, we report preliminary results in developing a high-specificity classifier. Our study also shows that FHR patients have specific MS and deregulate genes in unique pathways and biological processes as compared with GHR patients. This may provide insights into the biology and potential therapeutics of this group. Figure 1 Disclosures Chng: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria.