•Plerixafor, a CXCR4 antagonist, can mobilize and sensitize leukemia cells to cytotoxic therapy.•In our systematic review, preclinical studies confirm that leukemia cells can be mobilized.•Plerixafor ...can reduce tumor burden and improve survival of animals.•Clinical studies demonstrate relative safety and feasibility of using plerixafor.•Patients with high levels of CXCR4 expression on leukemia cells are worthy of future study.
Leukemia-initiating cells localize to bone marrow niches via cell surface CXCR4 binding to stromal-derived factor 1 (SDF-1). Plerixafor, a CXCR4 antagonist, can mobilize and sensitize leukemia cells to cytotoxic therapy, and/or enhance the engraftment of healthy donor stem cells in the context of hematopoietic cell transplantation (HCT). A systematic review of preclinical and clinical studies was performed (updated May 1, 2020) to inform the design of definitive clinical trials and identified 19 studies. Pooled data from 10 preclinical in-vivo studies of AML and ALL in mouse models of leukemia revealed significant mobilization of leukemia cells into the peripheral circulation, decreased total blast burden and increased survival with plerixafor in addition to cytotoxic treatment compared to control animals. Two of 9 clinical studies compared outcomes to a control group. Plerixafor appears well tolerated and safe and can mobilize leukemia cells into the peripheral circulation. In patients with AML undergoing HCT, plerixafor given with the conditioning regimen appears safe and well tolerated. Engraftment, relapse and survival were not different from controls after limited follow-up. Studies in high risk patients with AML with longer follow-up are needed to understand the influence on relapse following treatment and on donor cell engraftment following HCT.
Introduction: Outcomes of patients with relapsed or refractory multiple myeloma (MM) have improved substantially with access to novel therapeutic agents. However, patients with triple class exposed ...(TCE) MM continue to have poor outcomes. Though newer bispecific antibody and chimeric antigen receptor T-cell immunotherapies have improved outcomes of TCE patients, these therapies are inaccessible outside of clinical trials in many publicly funded healthcare systems, including Canada. This study aimed to describe treatment patterns, outcomes, unplanned health care utilization and quality-of-life impairments of TCE MM patients in Ontario, Canada. These data will provide a crucial benchmark to compare to as novel immunotherapies become available. Methods: This retrospective observational study utilized data from the Institute for Clinical Evaluative Sciences (IC/ES) administrative database, which contains all health records of patients treated within Ontario's publicly funded healthcare system. Drug exposure was determined using the Cancer Activity Level Reporting (ALR) and Ontario Drug Benefit Claims Registry (ODB) databases, housed within IC/ES, which contain data on intravenous and oral MM treatment exposure for standard of care and clinical trial regimens. Patients were defined as TCE if they had prior or current treatment with a regimen containing an immunomodulatory drug (lenalidomide or pomalidomide), a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib), and an anti-CD38 monoclonal antibody (isatuximab or daratumumab). The TCE index regimen was identified as the treatment on which a patient was first identified as having met the TCE definition. Inpatient hospitalization visits did not include planned chemotherapy infusion visits. Quality of life was described using the Edmonton Symptom Assessment System Score with scores ³ 7 corresponding to severe symptoms. Overall survival (OS) was determined using the Kaplan-Meier method. Results: Of the 16,777 patients with a diagnosis of MM between 2007-2021 in Ontario, 1358 patients were classified as TCE during their treatment course. The TCE index regimen was a daratumumab-based regimen in most patients daratumumab/velcade/dex (n=566, 42%), daratumumab/lenalidomide/dex (n=619, 46%). Of the TCE patients, 247 (18%) were still receiving treatment with the TCE index regimen at last follow up, 263 (19%) died without receiving any additional treatment, and 489 (36%) received a subsequent MM treatment after the TCE index regimen. Baseline characteristics of patients (n=489) treated with a subsequent MM regimen after post TCE are summarized in Table 1. The three most commonly administered therapies post TCE were carfilzomib-dexamethasone (n=111, 23%), pomalidomide-dexamethasone (n=77, 16%) and oral cyclophosphamide (n=49, 10%). The next-line treatment regimen was administered in an academic versus community treatment center in 235 (48%) versus 254 (52%) of patients, respectively. The next-line therapy was a clinical trial in only 37 (8%) patients. Regarding healthcare utilization, among TCE patients receiving subsequent therapy, 149 (30%) were evaluated in the emergency department (ED), 126 (26%) were admitted to hospital, and 48 (10%) were referred to palliative care while on treatment with the subsequent therapy. Among patients with available information, the most common severe patient-reported symptoms during the subsequent line of treatment included: tiredness (27%), pain (23%) and overall poor well-being (21%). Additionally, 35% of patients had a ECOG PS of ≥2 on next-line treatment. The median OS patients treated after the TCE index regimen was 1.05 year (95% CI 0.89-1.35) as shown in Figure 1. Of the patients that died during follow up, the majority died in hospital (n=147, 44%) and were referred to palliative care (217, 65%). Conclusion: In this real-world study, we showed that the overall outcomes of TCE MM patients remains poor in Canada, highlighting the urgent need for novel therapies. Furthermore, we demonstrated that TCE patients receiving subsequent therapy had significant unplanned health care utilization and poor quality of life. Future studies will need to assess whether the outcomes, healthcare utilization, and patient-reported quality of life improve as newer immunotherapies become accessible as standard of care treatments within our publicly funded healthcare system.
Introduction:
The routine incorporation of proteasome inhibitors, immunomodulatory drugs (IMIDs), and monoclonal antibody drugs (mAbs) in managing multiple myeloma (MM) has improved patients' ...prognosis. Unfortunately, triple refractory patients continue to do poorly. Immunotherapeutic approaches (mAbs, CAR-T cells) have shown the most promise in these patients. However, the efficacy of these therapies depends on a functional tumor immune microenvironment (iTME), which is extensively reshaped by existing MM therapies and disease evolution. Understanding how the iTME and malignant clone co-evolve over the disease course is crucial to optimize the use of immune-based treatments and understand their mechanisms of action.
Methods:
Newly diagnosed MM patients (NDMM), MM patients relapsing prior to anti-CD38 antibody exposure (RMM), and triple refractory MM patients (TRMM) were identified from the Mayo Clinic biospecimen database. We performed CyTOF (with a 37 marker lymphoid panel on CD138- bone marrow BM mononuclear cell samples) to assess the cellular iTME, Luminex (using BM plasma) to assess the humoral iTME (cytokines and chemokines) and RNAseq analysis (using BM CD138+ cells) to assess the malignant clone transcriptome. Astrolabe was used to identify immune cell clusters. Gene set enrichment analysis (GSEA) was used to identify gene pathways with differential expression across groups. JMP was used to perform unsupervised hierarchical clustering and descriptive statistics. An FDR corrected p value of <0.05 was considered statistically significant for all comparisons.
Results:
This study included 39 patients (13 NDMM, 11 RMM, and 15 TRMM). Samples were hierarchically clustered by cellular iTME, humoral iTME and malignant cell transcriptome, separately. The cellular iTME best recapitulated known disease biology and was used as the “anchoring” variable for subsequent analyses. Three distinct immune clusters were identified (figure 1): cluster 1, comprised mainly of NDMM and RMM patients; and clusters 2 and 3, comprised primarily of TRMM patients. In cluster 2, 4/5 patient samples were collected immediately after progression on daratumumab-IMID therapy, whereas all 7 TRMM patient samples in cluster 3 were collected at a median of 2.8 (range 0-17.2) months after last daratumumab exposure (table 1).
Most naïve T cell subsets (including the TIGIT+ T5 and the C38/CD127+ subsets T1, T2, and T12) were highest in cluster 1 compared to clusters 2 and 3. Several unfavorable T cell subsets were elevated in Cluster 2: 1) CD161+ T6, T7 and T17 subsets, which are thought to be Th17 polarized cells that promote MM growth; 2) T7, T9 CCR5+ subsets, which are thought to represent tumor-specific exhausted (PD-1+) T cell subsets; 3) senescent subsets (T-10, T14, T16,T18, T19); and 4) TCR-gd subsets with features of senescence (KLR, CD57), exhaustion (PD-1, TIGIT) and Th17 polarization (CD161).
There were no significant differences in cytokine and chemokine expression based on disease status (NDMM, RMM, or TRMM) or iTME (immune clusters 1, 2, or 3). GSEA was performed to compare clusters 2 and 3 (TRMM enriched) with cluster 1. The most up-regulated gene pathways in clusters 2 and 3 related to cell cycle targets of E2F transcription factors and MYC proliferation pathways. The most down-regulated gene pathways in clusters 2 and 3 were IFN-gamma, IFN-alpha and TNF-alpha response and signalling.
Conclusion:
Changes in the cellular iTME mirror the disease course better than changes in the malignant clone or humoral iTME. Patients with more refractory MM have a smaller pool of naïve T cells which express TIGIT or CD127 and could be “revived” with anti-TIGIT antibodies or IL-7 prior to manufacturing CART cells or administering BCMA-based therapies. Significant heterogeneity exists within the more refractory subgroups, with some patients having more dysfunctional T cell subsets which may be less responsive to immunotherapeutic approaches. The malignant transcriptome of samples in clusters 2 and 3 parallels the aggressive clinical course, with myc upregulation and downregulation of cytokine pathways that mediate an antitumor immune response. This study suggests that the MM iTME becomes more dysfunctional with therapy and may explain the differential sensitivity of patients to immunotherapeutic approaches.
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Kumar:MedImmune: Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Genecentrix: Consultancy; Sanofi: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Adaptive Biotechnologies: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Carsgen: Other, Research Funding; Novartis: Research Funding; Cellectar: Other; Kite Pharma: Consultancy, Research Funding; Karyopharm: Consultancy; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments.
BACKGROUND Given the poor prognosis and limited treatment options for patients with triple-class exposed/refractory multiple myeloma (TCE/R MM), there is a strong unmet need for novel interventions. ...Elranatamab, a B-cell maturation antigen (BCMA)- and CD3-directed bispecific antibody, recently demonstrated efficacy and safety in patients with TCE/R MM in the phase 2, single-arm MagnetisMM-3 trial (NCT04649359). The effectiveness of elranatamab was compared with physician's choice of treatment (PCT) in Canada through an unanchored matching-adjusted indirect comparison (MAIC), due to the absence of mature head-to-head comparative trial data. METHODS Individual patient data (IPD) from 14.7-month follow-up of MagnetisMM-3 (Cohort A BCMA- naïve N=123) was weighted to match published summary data from Canadian Myeloma Research Group (CMRG) database, which reported treatment patterns and outcomes on real-world patients with TCE/R MM in Canada (N = 199). Only BCMA-naïve patients from the MagnetisMM-3 trials were considered as BCMA therapies are not currently available as standard of care treatment options in Canada. To adjust for differences in baseline characteristics, patients from MagnetisMM-3 were reweighted to match those reported in the CRMG database. The adjustment variables were selected based on univariate Cox regressions using the MagnetisMM-3 IPD, a systematic literature review of prognostic variables and effect modifiers in relapsed or refractory MM, and a review of the recent analogous indirect comparisons, and confirmation by clinical experts. Weights were determined using a propensity score-type logistic regression via the method of moments (Signorovitch et al. 2012), based on age, median time since diagnosis, and number of prior lines of therapy. In the analysis for the endpoint of overall survival (OS), sex was also included in the analysis. A limitation of this MAIC is that key prognostic variables, such as International Staging System disease stage, cytogenetic risk, and extramedullary disease, were not adjusted for in the analysis as the definitions were not comparable between the data sources. Unanchored MAIC analyses used R code provided in the National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) 18 by Phillippo et al (2016). The respective outcomes in the MAIC were OS and progression-free survival (PFS) based on the 15-month follow-up data for elranatamab. Results were reported as hazard ratios (HRs) for time-to-event endpoints, with 95% confidence intervals (CIs). RESULTS Median PFS and OS was not reached in the MagnetisMM-3 trial. Patients with TCE/RMM treated with PCT had a median PFS of 4.4 months (95% CI 3.6 - 5.3) and a median OS of 10.5 months (95% CI 8.5 - 13.8). Following weighting, the summary statistics of key baseline characteristics were matched between elranatamab and CMRG. The effective sample size was 82 post-matching for PFS and 81 post-matching for OS. Compared with the patients in the CMRG database, elranatamab was associated with better PFS (HR: 0.36; 95% CI 0.23 - 0.54) and better OS (HR: 0.48; 95% CI 0.32 - 0.73). CONCLUSIONS In this MAIC, among TCE/R MM patients elranatamab demonstrated a significantly longer OS and PFS compared with PCT in the real-world setting reported in the CMRG database.
Introduction: Improvements in outcomes of patients with multiple myeloma (MM) depend on the use of regimens approved based on results from large phase III randomized controlled trials (RCTs) ...demonstrating their efficacy. However, many real-world (RW) patients would not have met the stringent RCTs inclusion criteria. Therefore, the effectiveness of these drugs in the RW setting is unknown. Understanding this efficacy-effectiveness gap is important to contextualize the expected outcomes in the current RW setting. Therefore, we conducted a retrospective population-based study to compare the efficacy versus effectiveness of registration RCTs with RW patients using standard of care (SoC) MM regimens for the primary outcomes of 1) progression free survival PFS; 2) overall survival OS and 3) serious adverse events (AEs). Methods: RW data was obtained from the Institute for Clinical Evaluative Sciences, an administrative database capturing all health records in the publicly funded health care system in Ontario, Canada. Adult patients treated between Jan 2007 to Dec 2020 with SoC regimens were included. Only regimens with corresponding registrational phase III RCTs which led to the public reimbursement in Ontario were included (lenalidomide/dex Rd and bortezomib/Rd VRd for newly diagnosed transplant ineligible patients, and relapsed MM (RRMM) regimens included carfilzomib/Rd KRd, carfilzomib/dex Kd, daratumumab/Rd DRd, daratumumab/bortezomib/dex DVd, pomalidomide/dex Pd). In the RW cohort, PFS was defined as the time from initiation of index regimen to death, initiation of subsequent MM treatment, or last follow-up, and patients remaining on the index regimen as last follow up were censored. Kaplan-Meier curves from pivotal phase 3 RCTs were manually digitized to provide individual patient-level estimates of PFS and OS. Meta-analyses were performed to compare the gap of PFS and OS outcomes of RW versus RCT patients, and effect estimates were summarized using hazard ratios (HR). The frequency of serious AE data was abstracted from published RCTs. Given that serious AEs in RCTs would have resulted in hospitalization, hospital admission during treatment with the index regimen was used as a surrogate for serious AEs in the RW cohort. Differences in RW and RCT safety outcomes were reported descriptively. Results & Discussion: A total of 3951 RW MM patients, treated with 7 standard of care MM regimens, were included. Baseline characteristics of patients in the RW and RCT cohorts are shown in table 1. Overall, patients in the RW cohort were older than in the RCTs. For relapsed regimens, there was a longer time between MM diagnosis and start of the regimen in the real-world versus RCT. With regards to the efficacy-effectiveness gap, MM patients treated in routine practise in the RW had a worse PFS despite overestimated of RW PFS compared to highly selected RCT patients for 6 of the 7 MM regimens evaluated, with a pooled HR of 1.44 (95% CI 1.34-1.54) in the meta-analysis (Figure 1A). Similarly, RW patients had a worse OS compared to RCT patients treated with 6 of the 7 regimens, with a pooled HR of 1.75 (95% ci 1.63-1.88) in the meta-analysis (Figure 1B). RRMM patients in the RW had higher rates of prior lenalidomide exposure compared to RCT patients. The only regimen which showed a trend towards performing better in the RW as compared to RCTs was Pd. The reason for this is likely multifactorial but perhaps patients included in the MM-003 RCT may have had more refractory MM (given the higher prior immunomodulatory drug exposure and longer time from diagnosis to treatment among Pd RCT patient) compared to RW patients in this study. With regards to safety, the percentage of patients with inpatient hospitalization during treatment in the real-world cohort and reported serious AEs in RCT were comparable (VRD 57% vs not reported NR; Rd 64% vs NR; Kd 57% vs 59%; KRd 53% vs 60%; DVd 36% vs NR; DRd 46% vs 49%; Pd 59% vs 61%). Conclusion: This is one the largest population-level studies highlighting the significant efficacy-effectiveness gap between registrational RCTs and RW usage of these regimens, with RW patients experiencing 44% worse PFS and 75% worse OS compared to RCT patients. Our data emphasize the importance of ongoing evaluation of RW data to contextualize effectiveness and toxicity of selected regimens in the clinic, and better inform both clinicians and patients for shared treatment decision making.
Developing prognostic tools specifically for patients themselves represents an important step in empowering patients to engage in shared decision-making. Incorporating patient-reported outcomes may ...improve the accuracy of these prognostic tools. We conducted a retrospective population-based study of transplant-ineligible (TIE) patients with multiple myeloma (MM) diagnosed between January 2007 and December 2018. A multivariable Cox regression model was developed to predict the risk of death within 1-year period from the index date. We identified 2356 patients with TIE MM. The following factors were associated with an increased risk of death within 1 year: age > 80 (HR 1.11), history of heart failure (HR 1.52), "CRAB" at diagnosis (HR 1.61), distance to cancer center (HR 1.25), prior radiation (HR 1.48), no proteosome inhibitor/immunomodulatory therapy usage (HR 1.36), recent emergency department (HR 1.55) or hospitalization (HR 2.13), poor performance status (ECOG 3-4 HR 1.76), and increasing number of severe symptoms (HR 1.56). Model discrimination was high with C-statistic of 0.74, and calibration was very good. To our knowledge, this represents one of the first prognostic models developed in MM incorporating patient-reported outcomes. This survival prognostic tool may improve communication regarding prognosis and shared decision-making among older adults with MM and their health care providers.
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