Go, Ronald S.

e20001 Background: High dose melphalan followed by autologous stem cell transplant (HDM-ASCT) remains the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) despite advances in treatments. Achievement of complete response (CR) is associated with improved overall survival (OS) and progression-free survival (PFS); Minimal Residual Disease (MRD) negativity (-) using next generation flow cytometry with a sensitivity of 10-5 is strongly associated with improved PFS and OS. We investigated the rates of conversion to MRD(-), especially MRD(-) CR following HDM-ASCT in patients with NDMM. Methods: We retrospectively reviewed patients with NDMM who underwent early HDM-ASCT at Mayo Clinic Rochester from May 2018 to July 2019. Response assessment was conducted after induction and within 100 days post-ASCT based on 2016 IMWG criteria, except for using Mass-Fix instead of immunofixation. MRD was assessed in bone marrow using the established Euro Flow protocol with sensitivity of 10-5. The FISH assay was used to risk-stratify patients as high-risk (HR) and standard risk (SR) cytogenetics as per the mSMART guidelines. Primary outcome measure was the conversion to MRD(-) CR after ASCT. Secondary outcomes include the overall conversion to MRD(-) irrespective of IMWG response, the impact of HR cytogenetics and pre-ASCT IMWG response on conversion to MRD(-) CR. Results: Two-hundred and ten patients were included; 126 (60%) were male and median age 62 years (range 32–77 years). There were 78 (44%) patients with HR cytogenetics. Pre-ASCT, 23 patients (11%) achieved MRD(-) CR, and 66 (31%) patients achieved MRD(-) CR post ASCT. Of 187 patients not in MRD(-) CR pre-ASCT, 45 (24%) converted to MRD(-) CR. Table provides a breakdown of the conversion rate of pre-ASCT IMWG response category to MRD(-) CR post ASCT and patients with MRD(+) CR had the highest rate (78%) of conversion. The presence of HR cytogenetics did not impact rates of MRD(-) CR achievement post ASCT irrespective of pre-ASCT IMWG response (p = 1.0). Overall, irrespective of IMWG response, 43 (20%) patients were MRD(-) pre-ASCT (19 in VGPR, 24 in CR or better) and 102 (49%) patients were MRD(-) post-ASCT (36 in VGPR, 66 in CR or better). Among 85 patients in VGPR post-ASCT, 36 were MRD(-) of which 8 (22%) progressed, while 49 were MRD(+) of which 24 (49%) progressed (p = 0.014). Conclusions: Upfront HDM-ASCT in patients with NDMM leads to deeper responses with 24% converting to MRD(-) CR and more than doubling of the total rate of MRD(-) irrespective of IMWG response. [Table: see text]

e19562 Background: Considerable healthcare resource utilization and financial burden have been associated with the treatment of Waldenstrom Macroglobulinemia (WM); however, the impact of health insurance status on patient outcomes has not been explored. We aimed to assess the insurance-based outcome relationship in WM using the National Cancer Database (NCDB). Methods: We analyzed patient-level data obtained from the NCDB, a database representing more than 70% of newly diagnosed cancer cases nationwide. All newly diagnosed WM cases (n = 8540) between 2004 to 2017 were identified. Only patients who underwent treatment were included. Insurance status was recorded by assessing the primary payer at the time of diagnosis. Due to Medicare eligibility criteria, age-based (< 65 and ≥65 years) stratified analysis was conducted. Cox proportional hazards model was utilized to analyze survival. Time-to-event analysis was conducted based on date-of-diagnosis using the Kaplan-Meier method and log-rank test. Results: Analysis was conducted on 3878 patients after meeting inclusion criteria, with a median follow-up time of 54.6 months. Among patients < 65 years (n = 1249; median age: 58 years; male: 62.4%), those with non-private insurance had inferior survival on multivariate analysis (Table) after adjusting for patient demographics, comorbidities, income, education, treatment center characteristics, and treatment start time. Significant overall survival (OS) differences were seen in those < 65 years (log-rank p < 0.001), with 5-year OS highest among patients with private insurance 91.2%, compared to Medicaid 79.8%, uninsured 77.4%, and Medicare 70.2%. In patients < 65 years, compared to private insurance, uninsured patients were more likely to be of Black race, reside in lower income areas, and be treated at non-academic centers (all p < 0.05). Both Medicaid and Medicare patients < 65 years were more likely to have a higher Charlson-Deyo comorbidity index (> 1) and live in areas of lower educational attainment and household income compared to private insurance (all p < 0.05). In patients ≥65 years (n = 2629; median age: 75 years; 60.6% males), no insurance-based OS (log-rank p = 0.096) differences were seen. Conclusions: Based on our study, significant insurance-based disparities exist in WM, where patients < 65 years old who are uninsured, or non-privately insured are at a higher risk of mortality. While the root cause of these differences is not fully elucidated, efforts should focus on ensuring that all patients have equal access to care regardless of primary payer status.[Table: see text]

6552 Background: Significant amounts of expensive oncology drugs are discarded resulting in waste and financial consequences for patients. Beginning in 2023, the Infrastructure Investment and Jobs Act (IIJA) will require drug manufacturers to refund Medicare for any single-use drugs where greater than 10% of the drug is wasted. We explored potential IIJA-associated savings through assessment of patterns in spending for discarded oncology agents between 2017-2020. Methods: We utilized the Medicare Part B Discarded Drug Units database from 2017-2020. Using J codes, we extracted spending and reimbursement data for discarded medications for antineoplastic and classical hematology therapies. The primary outcome was identification of therapies with high percentage of waste and the economic impact of retroactive application of the IIJA for discarded therapies. Results: Medicare Part B utilization data was extracted for a median 77 (64-152) oncologic therapies per year with median reimbursement for discarded treatments of $590 M ($566-616). From 2017-2020, bortezomib, romiplostim, and nab-paclitaxel were consistently among the top 5 therapies by value of wasted product. Pembrolizumab waste by value declined significantly after 2017 following transition to fixed dosing. In 2020, the top 5 therapies by value of wasted product were bortezomib, nab-paclitaxel, trastuzumab, romiplostim, and cabazitaxel with a value of $278 M. In 2020, the agents with the highest percentage of wasted product were bortezomib (27%), cabazitaxel (28%), decitabine (23%), topotecan (23%), and azacitidine (22%) with a collective discarded value of $160 M. Notably, these agents have weight-based dosing and single-use vials. Based upon the average number of drug claims per recipient and volume of product discarded, eliminating drug waste would allow an additional 6564 patients to receive treatment with discarded bortezomib. The number of additionally treated patients for the other top 5 agents: cabazitaxel (1216), decitabine (1509), topotecan (291), and azacitidine (2682). Retroactive application of IIJA policy would have impacted a median 20 (12-26) oncology agents resulting in median annual cost savings of $153 M (142-157) and the median annual spending on wasted oncology therapies would decline to $440 M (410-466). Conclusions: The IIJA would have yielded a median annual savings of $153 M in Medicare spending if applied retroactively. Given a 10% waste cutoff, a limited number of agents would be targeted by this legislation. In our study, we observe that drugs associated with weight-based dosing and single-use drug vials account for most drug waste. Strategies to minimize discarded units (through storage of unused product, approval of multi-dose vial formulations, or fixed-dose therapies) could yield substantial savings while enabling health equity in collaboration with communities with difficult access to these drugs.

110 Background: Sarcopenia or a loss of muscle mass increases with aging and is associated with increased overall mortality in patients with cancer. Recent advances in machine learning–based CNN algorithms have allowed for the rapid processing of digital images to produce image classifications of body composition. Since incidence of MM is highly associated with aging, we sought to determine if the presence of sarcopenia, as determined by utilizing this machine learning–based CNN algorithm on CT images, had prognostic value in patients with NDMM. Methods: We identified all patients with NDMM from January 2003 to July 2019 who had a standard-dose CT scan that included the L3 vertebral level performed within 6 months of diagnosis. Using a machine learning–based CNN-algorithm, abdominal CT images were analyzed to measure muscle area. These measurements were normalized by dividing the area values by the height of the patient squared (m2) to obtain skeletal muscle index (SMI) values. Patients were categorized as sarcopenic according to international gender-specific consensus cutoffs for SMI (male: < 55 cm2/m2 and female: < 39 cm2/m2). Patients with the following FISH cytogenetics were considered high risk (HR): t(4;14), t(14;16), t(14;20), and deletion 17p/monosomy 17 whereas the remainder were standard risk (SR). Survival analysis was performed using the Kaplan-Meier method and compared via the log-rank method. Results: The study cohort consisted of 344 patients. 68 (20%) were categorized as HR based on FISH cytogenetics.187 (54%) patients were sarcopenic based on their peri-diagnosis standard-dose CT scan. Sarcopenic patients were more likely to have ISS-3 disease (45% vs. 30%; p =.023), be male (73% vs. 48%; p <.001), and be ≥ age 75 (27% vs. 14%; p =.002) compared to non-sarcopenic patients. The median OS for patients with HR FISH and ISS 2 / 3 disease was 40 months and 57 months respectively compared to 90 months and 119 months for those with SR FISH and ISS-1 disease respectively (FISH: p <.004; ISS: p <.001). The median OS for sarcopenic patients was 44 months compared to 90 months for those not sarcopenic (p <.001). The time to next therapy (TTNT) for sarcopenic patients was 39 months compared to 45 months for those not sarcopenic (p =.05). In a multivariable model, the presence of sarcopenia (HR 1.64, 95% CI, 1.05–2.56; p =.03) retained significance in the presence of HR FISH, ISS 2 / 3 disease, and age ≥ 75. Conclusions: Gender-specific sarcopenia identified by a machine learning–based CNN algorithm significantly affects OS in patients with NDMM and is independent of age, ISS stage, and cytogenetic status. Future studies utilizing this machine learning–based methodology of assessing sarcopenia in larger prospective clinical trials are required to validate these findings.

PURPOSE: Precision oncology promises improved outcomes but the cost-effectiveness and accessibility of targeted therapies is debatable. We report price change patterns from 2015 to 2019 for several oral anticancer medications for common solid tumor malignancies. METHODS: We collected provider utilization and payment data from the public Medicare Part D database and extracted drug price information for commonly prescribed targeted oral anticancer agents for lung, breast, and prostate cancer. We then calculated median Pearson correlation coefficient values for various drugs (containing more than two data points) within each therapeutic class. We also calculated compound annual growth rates (CAGRs) for medication costs within each class and compared them with the consumer price index (CPI). RESULTS: Our study included six epidermal growth factor receptor inhibitors (EGFRi; one generic), five anaplastic lymphoma kinase inhibitors (ALKi), two B-Raf inhibitors (BRAFi), three hormonal agents (one generic), three cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), two poly-ADP-ribose inhibitors (PARPi), and seven antiandrogen agents (two generic). The median (range) Pearson correlation coefficient values for cost of drugs within each therapeutic class were 0.967 (0.915-0.978) for EGFRi, 0.981 (0.966-0.989) for ALKi, 0.996 for BRAFi, 0.994 (0.992-0.999) for CDK4/6i, 0.855 for PARPi, and 0.442 (–0.522 to 0.962) for antiandrogens. Therapies with two or fewer data points (generic erlotinib, dacomitinib, abiraterone, apalutamide, and darolutamide) were excluded. The median CAGRs in costs over the 5-year period were 4.56% (EGFRi), 6.40% (ALKi), 2.58% (BRAFi), 5.48% (hormonal agents), 5.21% (CDK4/6i), 27.29% (PARPi), and 34.8% (antiandrogens). The CPI over 5 years was 2.26%/year, and the average inflation rate was 1.90%/year. CONCLUSION: The median CAGR in costs for modern oral precision-driven cancer therapeutic classes mostly outpaced CPI and the average inflation. Increase in cost within the same class should be weighed against incremental clinical benefit for the patients to ensure that rising costs do not limit access to targeted therapies.

AbstractEculizumab is effective for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome. Although lifelong therapy had been suggested, discontinuation does not universally lead to relapse. Comprehensive data evaluating risk factors for recurrence following discontinuation are limited. Our aim was to systematically review available literature assessing the role of complement genetic variants in this setting. Reports on CM-TMA and eculizumab withdrawal published before 1 January 2021, were included. Key reasons for patient exclusion were no follow-up after drug withdrawal and patients lacking complement genetic testing. Two-hundred eighty patients from 40 publications were included. Median age was 28 years, and 25 patients had a known history of renal transplant. Complement genetic variants were identified in 60%, most commonly in CFH (n = 59) and MCP/CD46 (n = 38). Of patients with a complement gene variant, 51.3% had ≥1 likely pathogenic/pathogenic variant whereas the remaining had variants of uncertain significance (VUS). Overall relapse rate after therapy discontinuation was 29.6%. Relapse rate was highest among patients with CFH variants and MCP/CD46 variants in canonical splice regions. VUS (P &lt; .001) and likely pathogenic/pathogenic variants (P &lt; .001) were associated with increased relapse. Presence of a renal allograft (P = .009); decreasing age (P = .029); and detection of variants in CFH (P &lt; .001), MCP/CD46 (P &lt; .001), or C3 (P &lt; .001) were all independently associated with relapse after eculizumab discontinuation. Eculizumab discontinuation is appropriate in specific patients with CM-TMA. Caution should be exerted when attempting such a strategy in patients with high risk of recurrence, including a subgroup of patients with MCP/CD46 variants.

Abstract Langerhans cell histiocytosis (LCH) can affect children and adults with a wide variety of clinical manifestations, including unifocal, single-system multifocal, single-system pulmonary (smoking-associated), or multisystem disease. The existing paradigms in the management of LCH in adults are mostly derived from the pediatric literature. Over the last decade, the discovery of clonality and MAPK-ERK pathway mutations in most cases led to the recognition of LCH as a hematopoietic neoplasm, opening the doors for treatment with targeted therapies. These advances have necessitated an update of the existing recommendations for the diagnosis and treatment of LCH in adults. This document presents consensus recommendations that resulted from the discussions at the annual Histiocyte Society meeting in 2019, encompassing clinical features, classification, diagnostic criteria, treatment algorithm, and response assessment for adults with LCH. The recommendations favor the use of 18F-Fluorodeoxyglucose positron emission tomography-based imaging for staging and response assessment in the majority of cases. Most adults with unifocal disease may be cured by local therapies, while the first-line treatment for single-system pulmonary LCH remains smoking cessation. Among patients not amenable or unresponsive to these treatments and/or have multifocal and multisystem disease, systemic treatments are recommended. Preferred systemic treatments in adults with LCH include cladribine or cytarabine, with the emerging role of targeted (BRAF and MEK inhibitor) therapies. Despite documented responses to treatments, many patients struggle with a high symptom burden from pain, fatigue, and mood disorders that should be acknowledged and managed appropriately.

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to date been anecdotal. Here, we conducted a phase 1 clinical trial of systemic OV therapy and investigated the mechanisms of action in responding T-cell lymphoma (TCL) patients. A single IV dose of VSV-IFNβ-NIS was administered to patients with relapsed refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DL). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication and immune responses. Fifteen patients received VSV-IFNβ-NIS (7 multiple myeloma, 7 TCL, 1 acute myeloid leukemia); 3 patients were treated at each DL1 through DL3 (0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL4 (1.7 x 1011 TCID50). There were no dose limiting toxicities. 3 of 7 patients with TCL had RECIST responses: a 3-month PR at DL2, a 6-month PR and a durable CR ongoing at 20 months at DL4. Viremia peaked at the end of infusion and no infectious virus shedding was detected. Plasma interferon-β levels, a biomarker of VSV-IFNβ-NIS replication, peaked between 4h and 48h post infusion. The patient with CR had robust viral replication with increased ell free DNA in her plasma, a very high peak IFNβ level of 18,213 pg/ml, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. Further clinical testing is warranted. (This trial is registered at www.clinicaltrials.gov as NCT03017820).