ALBERT

Description: Introduction: Venous thromboembolism (VTE) is a common cause of morbidity and mortality among patients with multiple myeloma (MM). Thromboprophylaxis is a safe and effective way to decrease VTE in other high-risk populations. Recently, a clinical prediction model was developed to identify patients with newly diagnosed MM starting chemotherapy at highest risk of VTE. The model, IMPEDE VTE, found the following clinical risk factors for VTE: immunomodulatory drugs, body mass index, recent pathologic fracture of the femur or hip, erythropoietin stimulating drugs, dexamethasone, doxorubicin, Asian ethnicity/race, history of VTE, tunneled line or central venous catheter, and existing use of aspirin or anticoagulation. External validation of the model has yielded a c-statistic for VTE risk prediction of 0.64 to 0.65. Laboratory parameters can predict VTE in some patients with cancer. Accordingly so, the addition of laboratory parameters to IMPEDE VTE has the ability to improve model performance. Thus, we sought to determine the association between soluble P-selectin and D-dimer with the development of VTE in patients with newly diagnosed MM starting chemotherapy. Methods: We identified 545 patients from the Washington University in St. Louis MM banking protocol, with available plasma from time of diagnosis (2007-2019). Thirty-eight cases of VTE were identified within 6 months following treatment initiation. An additional 137 patients were randomly selected as controls. D-dimer and soluble P-selectin ELISA assays were performed on the banked plasma by Eve Technologies, who was blinded to case vs. control status. Both assays were performed in duplicate and results averaged. All additional variables were collected through manual chart abstraction. IMPEDE VTE scores were calculated as we previously described (Sanfilippo et al.). The association of D-dimer and soluble P-selectin with VTE risk was assessed using Cox regression, adjusting for IMPEDE VTE score. Results: The median age of all 545 patients was 65 (range 32-79), 54% were male, and 85% were white. All patients received novel chemotherapy agents for first-line MM therapy and 66% underwent autologous stem cell transplant. Of the 38 cases with VTE, 20 patients had deep vein thrombosis, 17 had pulmonary emboli, and 1 patient had concurrent events. The median time from chemotherapy initiation to VTE was 51 days (range 4-193). The median IMPEDE VTE score was 5 (range -1 to 12). Each unit increase in IMPEDE VTE score was associated with a 21% increase in risk for VTE (HR 1.21; 95% CI 1.04-1.40; p = 0.01). Median D-dimer was 11,795 ng/mL (range 280-144,832). Each 1000 ng/mL unit increase in D-dimer was associated with a 2% increase risk for VTE after controlling for IMPEDE VTE score (aHR 1.02; 95% CI 1.01-1.04; p 〈 0.001). Patients in the highest quartile of D-dimer levels, above the 75th percentile, had a 2-fold increase in risk of VTE after adjusting for IMPEDE VTE score (aHR 2.04; 95% CI 1.03-4.02; p = 0.04). Median soluble P-selectin was 189 ng/ml (range 23-638). There was no association between soluble P-selectin level and VTE risk in patients with MM. Conclusions and Relevance: D-dimer is predictive of VTE in patients with MM starting chemotherapy. The combination of D-dimer and the IMPEDE VTE score can improve identification of patients at high risk of VTE and therefore allow for selection of primary thromboprophylaxis among patients with MM. Disclosures Sanfilippo: Bayer HealthCare Pharamceuticals: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Other: Travel Support for Investigator Meeting; Pfizer: Membership on an entity's Board of Directors or advisory committees; Covington & Burling LLP: Consultancy; Luther & Associates: Consultancy; Health Services Advisory Group: Consultancy; Amgen: Other: Trasfer of Value (food) during discussion of research.

Description: Introduction: Currently, there are many 2nd-line treatment regimens for relapsed Multiple Myeloma (MM) but no standard therapy. Daratumumab, pomalidomide, and dexamethasone (DPd) is a newer 3-drug regimen approved by the FDA for treatment of multiple myeloma in the 3rd or later lines. The POLLUX trial reported a 12-month PFS of 83% in relapsed (median of one prior treatment line) MM treated with daratumumab, lenalidomide, and dexamethasone but excluded lenalidomide-refractory patients. A meta-analysis by Premkumar et al recently showed that high risk MM, del17p, t(4:14), t(14:16) cytogenetics, had minimal benefit from daratumumab-based therapies as 1st-line but benefited more in the 3rd-line or later setting. Nooka et al. previously reported increased response in daratumumab and pomalidomide naïve patients with relapsed refractory MM: median PFS of 41 months in a cohort of 12 patients. A recent Phase II trial by Siegel et al. demonstrated decreased efficacy of 2nd and 3rd-line DPd (1-year PFS of 45.2% vs 82.8% and ORR of 55.0% and 79.5%) in high risk versus standard risk patients respectively. However, it is unclear whether this pattern is consistent between patients treated with DPd in the 2nd vs 3rd-line. Herein, we report the efficacy of DPd when used in the 2nd versus 3rd-line depending on patient MSMART risk category. Methods: We reviewed pharmacy and institutional records of patients who began treatment with DPd in the 2nd (n = 33) or 3rd-line (n = 17) from April 2016 to March 2019. Patients had at least 1 year of follow up from starting DPd unless they progressed or expired before then. A line of therapy was defined as the therapy received between the events of diagnosis, progression, and/or death. We compared the ORR and 12-month PFS of 2nd-line and 3rd-line DPd. The differences in the 12-month PFS and ORR were compared using Fisher's exact test. Odds ratios (OR) were calculated from univariate/multivariate logistic regressions. Results: Thirty-three patients (23 men and 10 women), with median age of 63 (range 47 - 79) and median ECOG of 1, were treated with DPd as 2nd-line therapy. The 3rd-line DPd group was similar, consisting of 17 patients (14 men and 3 women), with median age of 62 (range 51 - 77) and median ECOG of 1. One patient was excluded from analysis in the 2nd-line group due to loss to follow up. Six patients were censored at time of transplant in the 2nd-line group: 4 (12.1%) received DPd as induction therapy for ASCT and 2 (6.1%) received DPd as maintenance therapy after ASCT. In the 3rd-line group, 2 (11.8%) received DPd as induction therapy and were censored. The most common side effects were cytopenias (35.3%), infections (15.2%), fatigue (8.8%). Most of the patients were daratumumab and pomalidomide naïve except one patient in the 3rd-line DPd group who had prior pomalidomide exposure. Twenty-two (66.7%) patients in the 2nd-line group were IMiD refractory versus 16 (94%) in the 3rd-line group. The 12-month PFS for the 2nd-line group was 40.6% compared with 64.7% in the 3rd-line group and showed a trend towards statistical significance (OR=2.82, p=0.09), and the difference reduced (OR=1.49, p=0.57) after adjusting for M-SMART risk category and t(4:14) cytogenetics. On exclusion of high risk and t(4:14), the 12-month PFS was 61.1% vs 66.7% for 2nd- and 3rd-line respectively (p〉0.99). The ORR was 84.9% in the 2nd-line group and 82.2% in the 3rd-line group (OR=1.34, p=0.74). The median follow-up for survivors were 22.3 months (range 2.5-43.4). 30 patients relapsed and 16 patients died during follow-up period. M-SMART high-risk designation (HR 2.56; 95%CI 1.09-6.04) and t(4:14) cytogenetics (HR 3.12; 95%CI 1.32-7.43) were associated with lower PFS. Older age of diagnosis was associated with a lower OS (HR 1.11; 95%CI 1.03-1.20). Conclusion: The difference in length of PFS between 2nd and 3rd- line DPd is likely an artifact of small sample size and differential efficacy of DPd depending on cytogenetics. Our results show comparable efficacy of 2nd to 3rd-line DPd when used in standard risk and non-t(4:14) intermediate risk MM. In patients with high risk or t(4:14) cytogenetics, it may be preferable to use DPd in the 3rd or later line. Disclosures Goldsmith: Wugen Inc.: Consultancy. Wildes:Carevive Systems: Consultancy; Janssen: Research Funding; Seattle Genetics: Consultancy. Schroeder:PBD Incorporated: Research Funding; Janssen: Research Funding; Dova Pharmaceuticals: Other; Astellas: Other; Gilead Sciences Inc: Other; GSK: Other; Celgene: Research Funding; Amgen: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Pfizer: Other; Genzyme Sanofi: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Partners Therapeutics: Other; Novo Nordisk: Other; Seattle Genetics: Research Funding; Fortis: Research Funding; Cellect Inc: Research Funding; Incyte Corporation: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Genentech Inc: Research Funding; FlatIron Inc: Other. OffLabel Disclosure: Daratumumab, pomalidomide, and dexamethasone is approved for treatment of relapsed, refractory multiple myeloma.

Description: Background Multiple myeloma (MM) is an incurable hematological malignancy of older adults. Autologous stem cell transplant (ASCT) remains a standard of care with multiple retrospective and registry cohort studies demonstrating its efficacy in MM patients including older adults with the disease. Despite this favourable data, there remains wide heterogeneity in the utilization of ASCT, particularly among older adults with MM. We conducted a mixed methods study from the perspective of both oncologists and older adults with MM to: 1) identify decision making factors that influence ASCT eligibility and 2) to explore any barriers to ASCT utilization. Methods We conducted a mixed methods study at two academic centres and two community centres in Ontario, Canada. Older adults with MM (aged 65-75) who were within one year of treatment decision making regarding ASCT were invited to complete a survey from outpatient clinics. Oncologists (both community & academic) were recruited via email. Semi-structured interviews were conducted with all participants who agreed to an interview. Thematic analysis was conducted to identify themes from the transcripts using NVivo (qualitative analytical software). The initial 3 transcripts were independently coded by two investigators, to develop a codebook. Any discrepancies were resolved using consensual validation. Once consensus was reached, the codes were then applied to the rest of the transcripts by one coder. A convergent parallel approach was used in combining the results of the qualitative and quantitative sections of the study. Results A total of 15 oncologists and 18 patients with MM completed the surveys. Baseline patient and oncologist characteristics are listed in Table 1. The majority of patients were offered an ASCT (78%) and among those offered, 79% went ahead with ASCT. Most patients were happy with the decision to either go ahead or refuse the transplant as indicated by a low decisional regret score (median of 5 and IQR of 0-19 out of 100, with a lower score indicating less regret with the decision). With regards to oncologists, 80% stated they were aware of geriatric tools to help with treatment risk stratification; however, the majority (75%) used none of these tools and relied on the 'eye-ball' test for decision making. Nine oncologists and 9 patients completed the semi-structured interview. Summarized themes identified are shown in Figure 1. From the perspective of patients, factors that most affected ASCT decision making were: strong trusting relationship with their oncologist (n=9), family support (n=9) and wanting the best treatment available (n=6). Top reasons to refuse ASCT were: fear of not recovering to baseline (n=2) and prolonged hospital stay (n=2). Oncologists identified using their clinical judgement (n=7), the belief that transplant was the best option (n=7) and lack of medical comorbidities (n=8), as the most important factors when recommending treatment. The lack of high quality randomized controlled trial data (n=9), local guidelines (n=5) and targeted assessment tools (n=7) were identified as barriers to ASCT. Notably, both patients (n=7) and oncologists (n=7) felt that ASCT decision making should not rely on chronological age alone. The findings of the qualitative and quantitative parts of the study concurred with each other and showed similar patterns. Conclusion To our knowledge, our study is the first to analyze contextual factors from the perspective of oncologists and older adults with MM that influence ASCT decision making and utilization. Despite guidelines supporting ASCT efficacy and safety among older adults with MM, our results demonstrate that the decision to undergo ASCT in older adults with MM is complex and variable both from the perspective of the patient and oncologist. Future incorporation of patient decision aids in parallel with enrollment of older adults in ASCT clinical studies and targeted geriatric assessments tools may provide an opportunity to enhance shared decision making and local guideline developments. Disclosures McCurdy: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Honoraria. Wildes:Carevive Systems: Consultancy; Janssen: Research Funding; Seattle Genetics: Consultancy. Mian:Sanofi: Consultancy; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy; Takeda: Consultancy, Honoraria.

Description: Carfilzomib is a critical chemotherapy medication used to treat patients with relapsed or refractory multiple myeloma. Unfortunately, drug-induced atypical hemolytic uremic syndrome (aHUS) has been established as a devastating and unpredictable side-effect of carfilzomib. Loss-of-function mutations in alternative complement pathway regulatory genes, such as complement factor H (CFH) and its related proteins (CFHRs), are the most frequently identified genetic abnormalities seen with aHUS. In our recently published work, two of three patients treated at the University of Rochester Medical Center for carfilzomib-induced aHUS were found to harbor the heterozygousCFHR3-CFHR1deletion, a genetic variant that is generally considered benign, implicating it in development of disease. We sought to further characterize the relationship between the heterozygousCFHR3-CFHR1deletion and development of carfilzomib-induced aHUS by conducting a case-control study. We screened banked frozen peripheral blood mononuclear cell (PBMC) samples from subjects treated with carfilzomib-based regimens at Washington University. Criteria for aHUS case selection were defined as all of the following: elevated LDH, decreased haptoglobin or elevated total bilirubin, evidence of schistocytes on peripheral blood smear, de novo anemia and thrombocytopenia, acute kidney injury, no evidence of infectious diarrhea (if tested), and active carfilzomib treatment at the time of disease. To ensure that controls had adequate exposure to carfilzomib, controls were selected from subjects who received ≥20 treatment cycles. Additional control selection criteria included: age 〉40 years, no evidence of hemolysis (LDH 100 x 109/L), and no chronic or acute kidney disease (creatinine

Description: Multiple myeloma (MM) is a hematological cancer of the antibody-secreting plasma cells. Despite therapeutic advancements, MM remains incurable due to high incidence of drug-resistant relapse. In recent years, targeted immunotherapies, which take advantage of the immune system's cytotoxic defenses to specifically eliminate tumor cells expressing certain cell surface and intracellular proteins have shown promise in combating this and other B cell hematologic malignancies. A major limitation in the development of these therapies lies in the discovery of optimal candidate targets, which require both high expression in tumor cells as well as stringent tissue specificity. In an effort to identify potential myeloma-specific target antigens, we performed an unbiased search for genes with specific expression in plasma and/or B cells using single-cell RNA-sequencing (scRNAseq) of 53 bone marrow samples taken from 42 patients. By comparing 〉40K plasma cells to 〉97K immune cells across our cohort, we were able to identify a total of 181 plasma cell-associated genes, including 65 that encode cell-surface proteins and 116 encoding intracellular proteins. Of particular interest is that the plasma cells from each patient were shown to be transcriptionally distinct with unique sets of genes expressed defining each patient's malignant plasma cells. Using pathway enrichment analysis, we found significant overrepresentation of cellular processes related to B-Cell receptor (BCR) signaling, protein transport, and endoplasmic reticulum (ER) stress, involving genes such as DERL3, HERPUD1, PDIA4, PDIA6, RRBP1, SSR3, SSR4, TXNDC5, and UBE2J1. To note, our strategy successfully captured several of the most promising MM therapeutic targets currently under pre-clinical and clinical trials, including TNFRSF17(BCMA), SLAMF7, and SDC1 (CD138). Among these, TNFRSF17 showed very high plasma cell expression, with concomitant sharp exclusion of other immune cell types. To ascertain tissue specificity of candidate genes outside of the bone marrow, we analyzed gene and protein expression data from the Genotype-Tissue Expression (GTEx) portal and Human Protein Atlas (HPA). We found further support for several candidates (incl. TNFRSF17,SLAMF7, TNFRSF13B (TACI), and TNFRSF13C) as being both exclusively and highly expressed in lymphoid tissues. While several surface candidates were not found to be lymphocyte-restricted at the protein level, they remain relevant considerations as secondary targets for bi-specific immunotherapy approaches currently under development. To further investigate potential combinatorial targeting, we examine sample-level patterns of candidate co-expression and mutually-exclusive expression using correlation analysis. As the majority of our detected plasma cell-specific genes encode intracellular proteins, we investigated the potential utility of these epitopes as therapeutic targets via MHC presentation. Highly expressed candidates include MZB1, SEC11C, HLA-DOB, POU2AF1, and EAF2. We analyzed protein sequences using NetMHC and NETMHCII to predict high-affinity peptides for common class-I and class-II HLA alleles. To correlate MHC allelic preference with candidate expression in our cohort, we performed HLA-typing for 29 samples using Optitype. To support our scRNAseq-driven findings, we cross-referenced gene expression data with 907 bulk RNA-sequencing samples, including 15 from internal studies and 892 from the Multiple Myeloma Research Foundation (MMRF), as well as bulk global proteomics data from 4 MM cell lines (TIB.U266, RPMI8226, OPM2, MM1ST) and 4 patients. We see consistent trends across both cohorts, with high positive correlation (Pearson R ranging between 0.60 and 0.99) for a majority of genes when comparing scRNA and bulk RNA expression in the same samples. Our experimental design and analysis strategies enabled the efficient discovery of myeloma-associated therapeutic target candidates. In conclusion, this study identified a set of promising myeloma CAR-T targets, providing novel treatment options for myeloma patients. Disclosures Goldsmith: Wugen Inc.: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.