Multiple Myeloma Survival Research Articles

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy.

Nuclear export proteins such as exportin-1 (XPO1) transport tumor-suppressor proteins and other growth-regulatory proteins from the nucleus to the cytoplasm. Overexpression of XPO1 has been observed in several cancers and correlates with shorter event-free and overall survival in multiple myeloma. Selinexor was developed as an oral first-in-class selective inhibitor of nuclear export (SINE) that inhibits XPO1. Preclinical studies in tumor cell lines and mouse models have demonstrated the efficacy of selinexor both as a single agent and in various combinations with known active antimyeloma agents. Results from the pivotal phase II STORM trial led to the US FDA approval of selinexor with dexamethasone in penta-refractory myeloma. Because of the feasibility of combining selinexor with other active antimyeloma agents, the multiarm STOMP trial was initiated and is ongoing, with impressive response rates reported in some of the combination arms thus far. The registrational phase III BOSTON trial demonstrated the superiority of selinexor in combination with bortezomib and dexamethasone as compared with bortezomib and dexamethasone in patients with relapsed refractory multiple myeloma (RRMM) who have received one to three prior anti-MM regimens. The toxicity profile of selinexor is wellestablished and predictable and may be significant unless managed aggressively and preemptively. The most common side effects are thrombocytopenia, anemia, neutropenia, fatigue, nausea, anorexia, and weight loss. Hyponatremia and cataracts seem to be class effects. Other SINE compounds are now being studied in efforts to discover agents that will potentially be better tolerated. Eltanexor is an investigational SINE compound that has shown a more positive toxicity profile in preclinical studies, with reduced central nervous system penetration and gastrointestinal side effects, and is now undergoing clinical investigation. These and other trials will further clarify the role of these innovative agents in the therapeutic advancement of RRMM.

The Association Between Low T3 Syndrome and Survival in Patients With Newly Diagnosed Multiple Myeloma: A Retrospective Study.

Objective: The correlation between low triiodothyronine (T3) syndrome and shorter survival in malignant tumor patients has been increasingly reported. The objective of the present study was to investigate the association between low T3 syndrome and survival in multiple myeloma (MM) patients. Methods: A total of 201 newly diagnosed MM patients were included in this retrospective study. All participants were divided into 2 groups based on serum free T3 (FT3) level: low T3 syndrome group (FT3 < 2.3 pg/mL) and non-low T3 syndrome group (FT3 ≥ 2.3 pg/mL). Baseline clinical characteristics, overall survival (OS) and progression free survival (PFS) were analyzed. Results: 80 (39.8%) patients had low T3 syndrome. Patients with low T3 syndrome had significantly lower blood hemoglobin and albumin, higher creatinine and β2-microglobulin (β2-MG), higher neutrophil/lymphocyte and (neutrophil + monocyte)/lymphocyte ratio, and more advanced ISS and R-ISS stages (all P < .05). Serum FT3 level was positively associated with blood hemoglobin and albumin, and negatively correlated with β2-MG, creatinine, neutrophil/lymphocyte ratio, and (neutrophil + monocyte)/lymphocyte ratio (all P < .05). Patients with low T3 syndrome had significantly inferior OS time and PFS time (both P < .001). In multivariate Cox analysis, low T3 syndrome was found to be an independent factor associated with OS (P < .001) and PFS (P = .002). Receiver operator characteristic curve analyses showed that FT3 was a predictive marker for death during the entire follow-up period (the area under the curve [AUC] = 0.720, P < .001) and during 1 year (AUC = 0.747, P < .001). Conclusion: Low T3 syndrome might be useful for predicting survival in patients with newly diagnosed MM.

POSB11 Correlation and Prognostic Value of Surrogate Endpoints and Overall Survival (OS) in Multiple Myeloma (MM): A Systematic Literature Review (SLR)

Emerging therapies in MM increase OS but also prolong time to mature OS data. This research aims to critically review and evaluate potential surrogate endpoints for OS in MM and to explore if these could be used to support health technology assessments (HTAs) for new therapies when mature OS data are unavailable.

Cardiovascular-specific mortality among multiple myeloma patients: a population-based study.

Introduction:Multiple myeloma (MM) survival has greatly improved in recent decades. MM is usually diagnosed at a median age of 66–70 years. MM patients do not necessarily die from primary cancer, so cardiovascular health may be a key factor threatening long-term survival. This study was designed to explore the cardiovascular disease mortality (CVM) trends in MM patients and compare them with those in the general population.Methods:In total, 88,328 MM patients from the Surveillance, Epidemiology, and End Results (SEER) database (1975–2016) were included. Standardized mortality ratios (SMRs) were used to assess CVM risk.Results:The CVM risk was significantly higher in MM patients than in the general population (SMR, 1.84 (95% CI, 1.78–1.89)). MM patients had the highest CVM SMR, at 2.62 (95% CI, 2.49–2.75), in the first year after diagnosis, and it decreased over the follow-up period. Over the study period, the incidence of CVM continued to decrease in MM patients diagnosed at age 65–74 (APC, −1.2% (95% CI, −1.9% to −0.4%)) and ⩾75 years (APC, −1.9% (95% CI, −2.6% to −1.2%)) but not younger. CVM was the second-most common cause of death in patients ⩾75 years. In only MM case analyses, male sex, Black race, older age at diagnosis, and earlier year of diagnosis were poor prognostic factors for heart-specific mortality.Conclusion:The CVM risk in MM patients was significantly higher than that in the general population. To improve survival, cardiovascular health should receive attention upon diagnosis.

Long term survival in multiple myeloma: a single institution experience in underprivileged circumstances

There is data suggesting that the clinical behavior of multiple myeloma (MM) may be different in Latin Americans than in Caucasian or African-Americans, consistent with a less aggressive course of MM in Latinos. We analyzed the overall survival (OS) of 139 persons with MM in a single institution in México, as well the variables which were associated with long-term OS. Of all patients, the median OS was 11 years whereas the 5-year and 10-year OS were 75% and 55% respectively. The analysis of variables showed that the variable related with five-year survival was having hematopoietic stem cell transplantation (HSCT), whereas the variables related with 10-year survival were HSCT, age at diagnosis (patients younger than 50 survived longer), light chain type (kappa survived longer) and ISS stage (stage I patients survived longer). The only variable associated with both 5 and 10-year survival was HSCT. A plateau in the OS was reached after 10 years, both in grafted and non-grafted patients. We have confirmed the critical role of HSCT in the prognosis of persons with MM, independent of the induction treatment or the maintenance post-transplant, and we have identified a better prognosis in this cohort, as compared with African-Americans or Caucasians, since the proportion of long-term survivors in our group is seemingly better than those in other populations

MRI-Based Bone Marrow Radiomics Nomogram for Prediction of Overall Survival in Patients With Multiple Myeloma.

PurposeTo develop and validate a radiomics nomogram for predicting overall survival (OS) in multiple myeloma (MM) patients.Material and MethodsA total of 121 MM patients was enrolled and divided into training (n=84) and validation (n=37) sets. The radiomics signature was established by the selected radiomics features from lumbar MRI. The radiomics signature and clinical risk factors were integrated in multivariate Cox regression model for constructing radiomics nomogram to predict MM OS. The predictive ability and accuracy of the nomogram were evaluated by the index of concordance (C-index) and calibration curves, and compared with other four models including the clinical model, radiomics signature model, the Durie-Salmon staging system (D-S) and the International Staging System (ISS). The potential association between the radiomics signature and progression-free survival (PFS) was also explored.ResultsThe radiomics signature, 1q21 gain, del (17p), and β2-MG≥5.5 mg/L showed significant association with MM OS. The predictive ability of radiomics nomogram was better than the clinical model, radiomics signature model, the D-S and the ISS (C-index: 0.793 vs. 0.733 vs. 0.742 vs. 0.554 vs. 0.671 in training set, and 0.812 vs. 0.799 vs.0.717 vs. 0.512 vs. 0.761 in validation set). The radiomics signature lacked the predictive ability for PFS (log-rank P=0.001 in training set and log-rank P=0.103 in validation set), whereas the 1-, 2- and 3-year PFS rates all showed significant difference between the high and low risk groups (P ≤ 0.05).ConclusionThe MRI-based bone marrow radiomics may be an additional useful tool for MM OS prediction.

Cost-effectiveness of adding daratumumab or bortezomib to lenalidomide plus dexamethasone for newly diagnosed multiple myeloma.

BACKGROUND: Multiple myeloma survival rates are steadily increasing due to availability of new drug classes used in combination with corticosteroids and chemotherapy. The latest treatments are daratumumab or bortezomib in combination therapy with lenalidomide and dexamethasone (Rd). Daratumumab, a CD38-targeted, human IgG1k monoclonal antibody, and bortezomib, a proteasome inhibitor, are both approved as regimens for transplant-ineligible relapsed/refractory multiple myeloma (RRMM). There have been cost-effectiveness analyses for daratumumab and bortezomib use in RRMM, but there are limited data regarding cost-effectiveness for daratumumab or bortezomib use in newly diagnosed multiple myeloma patients who are ineligible for stem cell transplantation. OBJECTIVE: To compare the cost-effectiveness of 3 separate regimens-(1) daratumumab, lenalidomide, and dexamethasone triple therapy (DRd); (2) bortezomib and lenalidomide plus dexamethasone triple therapy (VRd); and (3) lenalidomide plus dexamethasone (Rd)-in patients with multiple myeloma ineligible for autologous stem cell transplant. METHODS: A 2-state Markov model was developed using a US health system perspective and lifetime time horizon. Transition probabilities were calculated from the latest progression-free survival data reported in two phase 3 randomized controlled trials-MAIA and SWOG S0777-and extrapolated using a Weibull distribution based on the Hoyle Henley method. National data sources were used to obtain costs in 2019 US dollars, discounted by 3%. Health state utilities from available literature were applied to each health state. Utility decrements for adverse events were individualized in each choice branch with utility decrement weighted by the percentage of patients who experienced the adverse event in the MAIA and SWOG S0777 trials. We assumed a treatment would be cost-effective at a willingness to pay (WTP) of $150,000 per progression-free quality-adjusted life-year ($/PFQALY). One-way and probabilistic sensitivity analyses were conducted. RESULTS: Rd standard therapy had the lowest overall cost at $329,867, followed by VRd at $385,434 and DRd with the highest overall total cost at $626,900. Rd was estimated to result in the least amount (1.24) of PFQALYs, followed by VRd at 1.35 PFQALYs and DRd at 1.52 PFQALYs. With a WTP threshold of $150,000 per PFQALY, VRd was not cost-effective compared with Rd standard therapy, with an incremental cost-effectiveness ratio (ICER) of $530,256 per PFQALY. DRd was not cost-effective compared with VRd (ICER = $1,396,318 per PFQALY), nor as compared with Rd standard therapy (ICER = $1060,832). One-way sensitivity analysis showed that our model was sensitive to cost of DRd, VRd, and Rd drugs. Probabilistic sensitivity analysis showed that only at a WTP threshold of $550,000 was VRd cost-effective for 40% of iterations. There were no reasonable WTP thresholds, up to $800,00, where DRd became more cost-effective than VRd. CONCLUSIONS: This study is the first analysis to directly compare the cost-effectiveness of 3 acceptable chemotherapy treatment regimens for patients with multiple myeloma ineligible for autologous stem cell transplant. Neither DRd nor VRd triple therapy were found to be cost-effective vs Rd. Further cost-effectiveness analyses that include overall survival data for daratumumab and bortezomib triple therapies are needed to demonstrate an ICER in QALYs. DISCLOSURES: No funding was received for this study. At the time of this study, Narsipur was a UCSF-Actelion Clinical Research and Medical Communications Fellow, unrelated to this study. The other authors have nothing to disclose.

Shorter Survival in Multiple Myeloma Linked With Kidney Damage

Shorter Survival in Multiple Myeloma Linked With Kidney Damage

Family history of plasma cell disorders is associated with improved survival in MGUS, multiple myeloma, and systemic AL amyloidosis.

The association between familial plasma cell disorders (PCD) and prognosis in patients with MGUS, multiple myeloma (MM), and systemic light chain (AL) amyloidosis has not been well described. This study retrospectively reviewed outcomes of 25,423 patients (16,744 MGUS, 6194 MM, 2955 AL amyloidosis). Overall, 2.7% of patients reported having a family member with a PCD (defined as MGUS, MM, or AL amyloidosis). Family history was documented in 94% of MGUS, 92% of MM, and 88% of AL amyloidosis patients. The overall survival was consistently longer in patients with versus without familial PCD (crude hazard ratios: 0.52, 95% CI 0.40-0.67, p < 0.001 for MGUS patients; 0.68, 95% CI 0.57-0.79, p < 0.001 for MM patients; 0.60, 95% CI 0.43-0.84, p = 0.003 for AL patients). This association remained consistent when adjusting for baseline patient and disease characteristics. In MGUS patients, the risk of progression to MM, AL amyloidosis, or a lymphoproliferative disorder was higher in patients with familial PCD when accounting for death as a competing risk (cause-specific HR 1.9, 95% 1.3-2.7, p < 0.001). This is the first study to demonstrate that in a cohort of MGUS, MM, and systemic AL amyloidosis, patients with a PCD family history have an improved overall survival.

Second Primary Malignancies Among Patients with Multiple Myeloma

Introduction. Treatment for multiple myeloma (MM) has undergone significant transformation in the past decade with the introduction of novel therapeutic agents, including proteasome inhibitors (PI), immunomodulatory imides (IMiD) and monoclonal antibodies (mAb), leading to significant improvements in drug tolerability, treatment response and overall survival. As overall survival improves, patients with MM are at increased risk of developing second primary malignancies. Therefore, we evaluated the incidence of second primary malignancies among patients with MM.Methods. Using data from 30,630 1-year survivors of MM reported to 13 cancer registries that constitute the Surveillance, Epidemiology, and End Results (SEER) program (1992-2015; median survival time, 4.5 years), we calculated standardized incidence ratios (SIR) for all second primary malignancies, any solid and any hematologic malignancy and cancer sites among patients with MM, stratified by calendar year of first primary diagnosis consistent with advances in treatment for MM (1992-1999, 2000-2007, 2008-2015). Individual treatment data were unavailable. Excess absolute risk (excess cancer risk per 10,000 person-years) was calculated as ([observed cancers minus expected cancers]/person-years) multiplied by 10,000. Hazard ratios were calculated using Cox proportional hazards adjusted for confounders. Analyses were conducted using SAS v.9.4.Results. Overall, among 30,630 1-year survivors of first primary MM, the standardized incidence of any second primary malignancy was significantly increased (n=1,962; SIR=1.15, 95% confidence interval [CI], 1.10-1.20; P<0.0001) and SIRs were elevated in each of the three calendar periods (1992-1999, SIR=1.14; 2000-2007, SIR=1.11; 2008-2015, SIR=1.22). Of all the second primary malignancies, the incidence of any solid tumor was increased (n=1,584; SIR=1.05, 95% CI 0.99-1.10; P=0.09), albeit not significantly, with SIRs for specific solid tumor sites ranging from 0.80 to 2.23. In contrast, the incidence of any hematologic malignancy overall was significantly increased (n=317; SIR=2.28, 95% CI 2.03-2.54; P<0.0001) with the largest SIRs observed for any leukemia (SIR=5.86, 95% CI 4.91-6.94; P=<0.0001) and SIRs for leukemia subtypes ranging from 2.07 to 14.87. The SIR for any lymphoma was also increased but to a lesser extent (SIR=1.57, 95% CI 1.35-1.82; P<0.0001). Notably, SIRs for any leukemia decreased over the three time periods (1992-1999, SIR=6.40; 2000-2007, SIR=5.77; 2008-2015, SIR=5.51) whereas SIRs for any lymphoma increased (1992-1999, SIR=1.21; 2000-2007, SIR=1.60; 2008-2015, SIR=1.81) leading to an excess absolute risk of any hematologic malignancy of 1.5 per 10,000 person-years in the latest calendar period. No differences were observed by sex or ancestry.Discussion. We confirm that MM patients are at increased risk of second primary malignancies, and particularly other blood cancers. The transposition of leukemia and lymphoma incidence over time may reflect the effect of treatment changes in recent years. Additional studies, which include individual treatment data and longer follow up time from large and diverse populations, are required to further define these relationships. DisclosuresNo relevant conflicts of interest to declare.

Exploring Interest in and Feasibility of a Lifestyle Intervention for Multiple Myeloma Patients

Exploring Interest in and Feasibility of a Lifestyle Intervention for Multiple Myeloma Patients

Chromatin Remodeling and Associated Changes in Gene Expression Induced By Bone Marrow Stromal Cells Identify Features of High-Risk Multiple Myeloma

Introduction: Stromal cells in the bone marrow microenvironment maintain a complex bidirectional relationship with the malignant plasma cells and have been implicated in the growth and survival of multiple myeloma (MM) cells along with the development of drug resistance and disease progression. We hypothesized that the perpetual induction of gene expression changes similar to those induced by stromal interactions may lead to an aggressive disease phenotype and possible stromal independence. We investigated the chromatin remodeling and associated gene expression changes in malignant plasma cells induced by stromal cells and applied the findings to large sets of patient data.Methods: We interrogated the chromatin accessibility (ATAC-seq) and gene expression profiles (RNA-seq) of malignant plasma cells (INA6, MM1S, RPMI) after co-culture with stromal cells (HS5). We identified de novo accessible enhancers and associated them with their putative target genes within conserved topologically associating domains based on their proximity in the linear genome. The in vitro data were then applied to data from patients with newly diagnosed MM (n=559). Using proportional hazards regression and automated feature selection algorithms we selected 10 of the 68 overexpressed target genes based on their association with progression-free survival. We devised a dichotomous classifier based on the expression of these 10 genes and validated its independent prognostic significance and ability to predict therapeutic resistance in two additional patient cohorts (n=214 and n=635, respectively). We applied gene set enrichment analysis to interrogate whether the gene expression profile induced by these adverse stromal interactions recapitulates the transcriptional program of extramedullary malignant plasma cells using single-cell RNA-seq.Results: Co-culture of malignant plasma cells with stromal cells induced widespread chromatin remodeling including de novo accessibility of known cis-regulatory elements and the overexpression of their putative target genes (68 overexpressed genes with associated accessible enhancers, overlap p=1.05x10 -13). The expression of 10 of these 68 genes was independently associated with progression-free survival in the UAMS TT2/3 data set (n=559). A summary measure of the expression of these 10 genes was dichotomized to classify approximately 30% of patients as having adverse stromal interactions (ASI+). The 10-gene ASI+ classifier was associated with overall survival in three independent patient cohorts with newly diagnosed MM: UAMS TT2/3 (29% ASI+, HR 1.93, 95% CI 1.43-2.62, p<0.001, n=559), IFM 2009 (32% ASI+, HR 2.61, 95% CI 1.67-4.10, p<0.001, n=214), and MMRF IA16 (30% ASI+, HR 1.69, 95% CI 1.29-2.24, p<0.001, n=635). Its prognostic significance was independent of age, sex, ISS stage, elevated LDH, high-risk cytogenetics, and the high-risk transcriptomic classifiers (UAMS-70, EMC-92). The 10-gene ASI+ classifier predicted resistance to first-line therapy in general and to treatment with VRd in particular (OR 1.64, 95% CI 1.10-2.43, p=0.015, MMRF IA16, n=211). Gene set enrichment analysis demonstrated that the gene expression profile of patients with ASI+ recapitulates the transcriptional program of extramedullary malignant plasma cells (5376 circulating plasma cells, NES 1.41, FDR=0.027; 477 plasma cells from malignant effusions, NES 1.37, FDR=0.029). This extramedullary-like gene expression pattern translated into a higher prevalence of circulating plasma cells among newly diagnosed ASI+ patients (54% versus 35%, p=1.65x10 -5, MMRF IA16, n=629) and a higher incidence of bone disease and plasmacytoma progression during follow-up (HR 2.24, 95% CI 1.51-3.31, p<0.001, MMRF IA16, n=622).Conclusions: We identified permissive chromatin states and associated transcriptional programs induced by the interactions between MM cells and bone marrow stromal cells. The constitutive induction of genes in the malignant plasma cells of patients with newly diagnosed MM supported transcriptional programs associated with therapeutic resistance, accelerated disease dissemination, and impaired long-term survival. These changes may allow MM cells to acquire the capacity to sustain extramedullary growth. The development of novel therapeutic approaches to overcome these adverse stromal interactions remains an unmet need in patients with MM. DisclosuresMunshi: Adaptive Biotechnology: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Novartis: Consultancy; Legend: Consultancy; Pfizer: Consultancy.

Racial and Age-Related Differences in Impacts of High-Risk Cytogenetic Abnormalities on Survival in Multiple Myeloma in a Nationwide Electronic Health Record-Derived Database

Background: The incidence of multiple myeloma (MM) and enrichment of cytogenetic abnormalities differ significantly between racial/ethnic groups in the US, and their significance in determining myeloma progression and survival is not well understood. Whole genome sequencing has identified unique mutational signatures in MM, including an age-related process common in hyperdiploid myeloma. Our purpose was to describe racial and age-related differences in the impact of high-risk cytogenetic abnormalities (HRCAs) on survival in MM.Methods: We conducted a retrospective cohort study of adult MM patients starting first-line therapy between January 2011 and May 2021 using the nationwide Flatiron Health electronic health record-derived de-identified database. Patient-level demographic and clinical characteristics were ascertained using structured and unstructured data, curated via technology-enabled abstraction. Patients who had documented fluorescence in situ hybridization testing within 30 days prior to or 90 days following the start of first-line treatment were included. HRCAs, including gain or amplification 1q21, deletion 17p, t(4;14), t(14;16) and t(14;20), were identified and categorized as 0, 1, or 2+ HRCAs. Our outcomes of interest were real world progression free survival (rwPFS) and overall survival (rwOS). Cox proportional hazards models were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI), adjusted for demographic and clinical characteristics and treatment including time-dependent receipt of autologous stem cell transplantation.Results: From a cohort of 4889 MM patients, there were 790 (16%) Black and 2995 (61%) White patients with median ages at diagnosis of 68 and 70 years, respectively. Compared to White patients, a higher proportion of Black patients had IgG M-protein (61% vs 55%) and a lower proportion had 1+ HRCAs identified (31% vs 34%). Among all racial groups, compared to patients aged <65 years (N=1771), a higher proportion of patients aged 65+ years (N=3118) had IgA M-protein (21% vs 17%) and 1+ HRCAs identified (35% vs 33%).Multivariable models showed evidence of significant statistical interaction between age and prevalence of HRCA for rwPFS (P-int: 0.02). Among White patients, having 2+ HRCAs (“double-hit MM”) compared to no HRCAs was associated with worse rwPFS in both younger and older patients (<65 years: HR 2.88, 95% CI 1.93-4.32, P<0.01; 65+ years: HR 1.51, 95% CI 1.18-1.94, P<0.01). Among Black patients, associations between double-hit MM and rwPFS were attenuated and not statistically significant regardless of age (<65 years: HR 1.81, 95% CI 0.69-4.74, P=0.23; 65+ years: HR 1.61, 95% CI 0.92-2.81, P=0.09).Similarly, we also found evidence of statistical interaction between age and prevalence of HRCA for rwOS (P-int: 0.02). Among White patients, double-hit MM was significantly associated with worse rwOS but the magnitude of increased risk differed for younger (HR 3.39, 95% CI 2.24-5.14, P<0.01) and older (HR 1.61, 95% CI 1.27-2.05, P<0.01) patients. Double-hit MM was significantly associated with worse rwOS among older Black patients (HR 1.78, 95% CI 1.03-3.06, P=0.04), but not younger Black patients (HR 1.60, 95% CI 0.58-4.40, P=0.36).Conclusions: In this cohort of newly diagnosed MM patients treated in routine practice, having double-hit MM was differentially predictive of poor survival across age groups. Double-hit MM was associated with worse rwPFS and rwOS among White patients, but these trends were less consistent among Black patients. Our current understanding of cytogenetic risk stratification of MM requires further study and additional data for identifying low- and high-risk subsets of patients across different ages and racial groups.Figure. Kaplan-Meier survivor functions for rwPFS in White (Panel A) and Black (Panel B) patients by age group and number of HRCAs [Display omitted] DisclosuresCalip: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company; Pfizer: Research Funding. Ascha: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company. Wang: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Pierre: Flatiron Health, Inc: Current Employment; Roche: Current holder of stock options in a privately-held company. Maignan: Flatiron Health: Current Employment; Roche: Current equity holder in publicly-traded company. Wadé: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Leng: Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment. Seymour: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Current equity holder in publicly-traded company; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Flatiron Health Inc: Current Employment. Patel: Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Neparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding.

Variation in Use of Immunoglobulin and Impact on Survival in Multiple Myeloma: A Report from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR)

Variation in Use of Immunoglobulin and Impact on Survival in Multiple Myeloma: A Report from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR)

Characteristics Associated with Disparities in Survival between Hispanic and Non-Hispanic White Patients with Multiple Myeloma: A Matched Cohort Study

Characteristics Associated with Disparities in Survival between Hispanic and Non-Hispanic White Patients with Multiple Myeloma: A Matched Cohort Study

Relapsed/Refractory Multiple Myeloma Patients. a Multicenter Retrospective Analysis of Eligibility Criteria for CAR-T Cell Therapy

Background. The overall survival (OS) of multiple myeloma (MM) patients (pts) has improved over the years due to the introduction of several novel drugs, such as proteosome inhibitors (PI), immunomodulatory drugs (IMiDs) and, more recently, anti-CD38 monoclonal antibodies (moAb). Nevertheless, the majority of pts continues to relapse, and MM remains an incurable disease. To date, no standard of care has been established for relapsed/refractory (RR) MM pts who have been exposed to the main anti-myeloma drugs. Currently, these pts have a limited number of available treatment options and represent an unmet medical need. Moreover, the outcome of pts failing standard of care regimens, which is now defined as triple-refractory (including PI, IMiDs and moAb), is poor, with a median progression free survival (PFS) of 3-4 months and OS of 8-9 months. Novel therapeutic strategies with different mechanisms of action are warranted to overcome the natural occurrence of relapse or therapy resistance in RR MM pts. Immunotherapy, especially T-cell based approaches, represents the emerging therapeutic strategy for this subset of pts. Chimeric antigen receptor (CAR)-modified T cells are a promising new therapy approach for triple refractory RRMM. Different constructs and specific CAR-T targets are being studied, but BCMA-directed CAR-T cells have so far provided the most convincing evidence of activity, with one product (idecabtage vicleucel) recently approved by FDA.Aims. The primary endpoint of this observational and retrospective study was to define the clinical characteristics and outcome of a cohort of RR MM pts potentially eligible to CAR-T cell treatment according to the KarMMa trial criteria 1. Secondary endpoints were aimed at defining specific factors influencing CAR-T cell therapy eligibility and at identifying a real-life estimate of RRMM pts truly eligible for CAR-T cells.Methods and Results. This is a cohort analysis that used electronic REDCap, a data capture tool hosted at the Sapienza University, on RRMM pts managed between January 2018 and July 2021 at 4 Italian Centers of the Multiple Myeloma GIMEMA Lazio Group. At the time of data collection, 47 RRMM pts had underwent at least 3 prior therapy regimens; they had received a previous PI, IMiDs and a moAb and were considered refractory to the last regimen. The clinical characteristics are listed in Table 1. Median age was 68 years (43-86), 27 (61%) pts were >65 years; 27 (57%) were male. Of 47 pts, 33 (68%) were ECOG 0-1 and 14 (30%) were ECOG ³2; 21 pts (44%) were ISS III. The majority of pts, 28 (59%), had undergone an autologous stem cell transplantation; 31 pts (65%) had received 3 prior lines of therapy and 16 (34%) >3 prior lines of therapy. Thirty-seven (78%) were triple-refractory and 8 (17%) were penta-refractory. Based on the KarMMa trial criteria, 22/47 pts (47%) would be defined as eligible and 25 (53%) not eligible for CAR-T cell therapy. Specifically, 14 (30%) pts were not eligible because of an ECOG ³2, 24 (62%) had an organ dysfunction such as impaired renal function (eGFR <45 ml/min/1.73m 2), anemia and thrombocytopenia. Of the 25 pts considered ineligible for CAR-T cell therapy, 17 (68%) presented ≥2 ineligibility criteria. The entire cohort of 47 pts had a negative hepatitis and HIV serology, and no patient had previously undergone anti-BCMA therapy or an allogeneic stem cell transplantation.After a median follow-up of 34.7 months (mo) (0-53.8), the median OS for the entire cohort was 21.7 mo (95% CI: 14.2-36.9) (Fig. 1). The median OS was 30.7 mo (95%, CI: 14.21-NA) in eligible pts vs 16.2 mo (95%, CI: 6.28-NA) in non-eligible pts (p=0.002) (Fig.2). The median PFS of the entire cohort was 7.7 mo (95%, CI: 5.39-13.85) (Fig. 3) and the median PFS was 7.8 mo (95%, CI: 5.16-19.1) in eligible pts vs 6.5 mo (95%, CI: 3.36-NA) (p=0.513) in non-eligible pts (Fig.4).Conclusions. Despite the limits of a retrospective study and a limited cohort, our real-life analysis shows that heavily treated pts with RRMM are less likely to be eligible for CAR-T cell therapy. Considering the emergent role of quadruplet combined approaches for first-line therapy and given the therapeutic relevance of CAR-T cells for the management of RRMM pts previously exposed to PI, IMiDs and moAb, our data could help to better define pts who could benefit from CAR-T cells under the current indications, while waiting for an extension of this approach to earlier disease stages.1. N Engl J Med 2021;384:705-16 [Display omitted] DisclosuresFazio: Janseen: Honoraria. Caravita di Toritto: celgene: Other: travel expenses, Research Funding; Janseen: Other: travel expenses, Research Funding; amgen: Other: advisory board; takeda: Research Funding; GSK-SANOFI: Other: advisory board. Martelli: Gilead: Other: advisory board; Novartis: Other: advisory board. Petrucci: Janssen-Cilag: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board.

Impact of Treating Facility on Overall Survival and Treatment in Multiple Myeloma (MM) Using National Cancer Database (NCDB)

Introduction:Prior studies have shown poorer outcomes in Black and Hispanic patients and in patients with lower median household income and education 1-5. In MM, we hypothesize that facility affiliation and case volume affects overall survival (OS) and rates of frontline treatment (including chemotherapy, immunotherapy, autologous stem cell transplant [ASCT] and palliative care).Methods:This is a retrospective analysis of 174,551 MM patients in the NCDB database, over the age of 18 years, between 2004-2016. Facility types include community cancer programs, comprehensive community cancer programs, academic/research cancer programs and integrated network cancer programs. High volume facilities had new MM cases per year ≥ 99 th percentile, and all other facilities were classified as low volume. Multivariable analyses used Cox proportional hazard analysis for OS and logistic regression for use of treatment, adjusted for age, sex, race, Hispanic origin, education, great circle distance, CCI score, and type of county (depending on population size). Kaplan-Meier method was used to estimate median OS, and the log rank test was used to compare OS across predictor variables.Results:The median age was 67 years (range 18-90) with 55% males, and 76% White vs 20% Black. In academic/research cancer programs, the median OS in high volume centers was 75.5 mo vs 50.2 mo in low volume centers (p<0.01). In community cancer programs, the median OS in high volume centers was 55.2 mo vs 35.5 mo in low volume centers (p<0.01). In multivariable analyses, the OS was higher in academic/research cancer programs vs community cancer programs (hazard ratio of 0.87 p<0.01). There was no significant difference in OS at integrated network cancer programs or comprehensive community cancer programs vs community cancer programs. The odds of utilizing chemotherapy were higher in academic/research cancer programs compared to community cancer programs (p<0.01 for both), whereas the odds of receiving palliative care were similar between both facility types (p=0.25). The odds of utilizing ASCT were higher in all facilities when compared to community cancer programs (p<0.01). The odds of utilizing palliative care were higher at integrated network cancer programs and comprehensive community cancer programs compared to community cancer programs (p<0.01 for both). Facilities with low volume of cases had significantly lower odds of utilizing chemotherapy, immunotherapy and ASCT when compared to high volume facilities; however had significantly increased odds of receiving palliative care.Discussion:Our results show that academic/research cancer programs with high volumes have the best OS in MM. Additionally, academic/research cancer programs are more likely to give chemotherapy, immunotherapy, and ASCT, but less likely to give palliative care. We theorize that academic/research cancer programs with a high volume of cases likely have increased resources, which optimizes outcomes. Given that ~25% of patients with MM die in the first year 6, there is a recognized need to identify strategies to improve early outcomes in patients treated at community cancer programs and low volume facilities. [Display omitted] DisclosuresLai: Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees.

A Novel Risk Scoring System to Predict Survival in Soft Tissue-Related Extramedullary Multiple Myeloma

Objective:Extramedullary multiple myeloma (EMM) is an aggressive subtype of multiple myeloma, especially those soft tissue-related extramedullary multiple myeloma (EM-S). Plasma cells often infiltrate in extramedullary tissues, but the proportion of plamas cells in bone marrow is not high, so FISH test often produces false negative results. Therefore, the R-ISS staging system cannot predict the really prognosis of this type of patients. A novel risk score is needed for these patients.Methos: A cohort of 73 patients with EM-S in four centers in China were included, excluding those only with bone related extramedullary multiple myeloma, primary or secondary plasma leukemia. We performed univariate and multivariate Cox regression analysis, generated risk scores to predict outcomes in EM-S MM and compared with R-ISS staging.Results: In the Cox multivariate model, high LDH, low count of platelet、central nervous system involved, abdominal viscera involved (including liver, spleen, pancreas, kidney) and Ki67≥70% were found to significantly and independently predict outcomes for EM-S. According to these parameters, the patients were divided into three groups: the low-risk group with a median TTP of 14.13 months, and the medium-risk group with a median TTP of 8.53 months. In the high-risk group, the median TTP was 2.73 months (p<0.05 between any two groups). This novel risk is better to predict prognosis of this group of patients than R-ISS stage, in which the TTP in R-ISS stage I was 20.33 months, R-ISS stage II 9.83 months, and R-ISS stage III 4.83 months (p=0.065). Conclusion: The novel risk stratification for EM-S may be may be superior to R-ISS for EM-S MM patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Foot drop in patients treated with bortezomib – a case series and review of the literature

Bortezomib-induced peripheral neuropathy (BIPN) has a profound impact on quality of life, which is an important issue considering the growing number of survivors of multiple myeloma and amyloidosis. BIPN is typically symmetric, distal, "stocking and glove" distribution and predominantly consists of sensory rather than motor symptoms. In this case series, we report an acute neurotoxicity syndrome induced by bortezomib, which is clinically distinct from BIPN by not being peripheral and distal. We describe six patients that developed unilateral or bilateral foot drop attributed to bortezomib. With bortezomib discontinuation symptoms improved gradually over months to years.

Influence of Sex in the Molecular Characteristics and Outcomes of Malignant Tumors.

BackgroundSex is frequently underestimated as a prognostic biomarker in cancer. In this study, we evaluated a large cohort of patients and public datasets to determine the influence of sex on clinical outcomes, mutational status, and activation of immune pathways in different types of cancer.MethodsA cohort of 13,619 Oncosalud-affiliated patients bearing sex-unrelated cancers was followed over a 20-year period. Hazard ratios (HRs) for death were estimated for female vs. male patients for each cancer type and then pooled in a meta-analysis to obtain an overall HR. In addition, the mutational status of the main actionable genes in melanoma (MEL), colorectal cancer (CRC), and lung cancer was compared between sexes. Finally, a gene set enrichment analysis (GSEA) of publicly available data was conducted, to assess differences in immune processes between sexes in MEL, gastric adenocarcinoma (GC), head and neck cancer (HNC), colon cancer (CC), liver cancer (LC), pancreatic cancer (PC), thyroid cancer (TC), and clear renal cell carcinoma (CCRCC).ResultsOverall, women had a decreased risk of death (HR = 0.73, CI95: 8%–42%), with improved overall survival (OS) in HNC, leukemia, lung cancer, lymphoma, MEL, multiple myeloma (MM), and non-melanoma skin cancer. Regarding the analysis of actionable mutations, only differences in EGFR alterations were observed (27.7% for men vs. 34.4% for women, p = 0.035). The number of differentially activated immune processes was higher in women with HNC, LC, CC, GC, MEL, PC, and TC and included cellular processes, responses to different stimuli, immune system development, immune response activation, multiorganism processes, and localization of immune cells. Only in CCRCC was a higher activation of immune pathways observed in men.ConclusionsThe study shows an improved survival rate, increased activation of immune system pathways, and an enrichment of EGFR alterations in female patients of our cohort. Enhancement of the immune response in female cancer patients is a phenomenon that should be further explored to improve the efficacy of immunotherapy.